Modulators of the prostacyclin (pgi2) receptor useful for the treatment of disorders related thereto

ABSTRACT

The present invention relates to amide derivatives of Formula (XIIIa) and pharmaceutical compositions thereof that modulate the activity of the PGI2 receptor. 
     
       
         
         
             
             
         
       
     
     Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of: pulmonary arterial hypertension (PAH); idiopathic PAH; familial PAH; PAH associated with a collagen vascular disease, a congenital heart disease, portal hypertension, HIV infection, ingestion of a drug or toxin, hereditary hemorrhagic telangiectasia, splenectomy, pulmonary verso-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis (PCH); PAH with significant venous or capillary involvement; platelet aggregation; coronary artery disease; myocardial infarction; transient ischemic attack; angina; stroke; ischemia-reperfusion injury; restenosis; atrial fibrillation; blood clot formation in an angioplasty or coronary bypass surgery individual or in an individual suffering from atrial fibrillation; atherosclerosis; atherothrombosis; asthma or a symptom thereof; a diabetic-related disorder such as diabetic peripheral neuropathy, diabetic nephropathy or diabetic retinopathy; glaucoma or other disease of the eye with abnormal intraocular pressure; hypertension; inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis; Crohn&#39;s disease; transplant rejection; multiple sclerosis; systemic lupus erythematosus (SLE); ulcerative colitis; ischemia-reperfusion injury; restenosis; atherosclerosis; acne; type 1 diabetes; type 2 diabetes; sepsis; and chronic obstructive pulmonary disorder (COPD).

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/848,746, filedApr. 14, 2020, which is a division of U.S. Ser. No. 15/447,573, filedMar. 2, 2017, now U.S. Pat. No. 10,668,033, issued Jun. 2, 2020, whichis a continuation of U.S. Ser. No. 14/510,669, filed Oct. 9, 2014, nowabandoned, which is a division of U.S. National Phase application Ser.No. 12/933,196, filed Oct. 14, 2010, now U.S. Pat. No. 8,895,776, issuedNov. 25, 2014, which is a § 371 National Phase Application ofInternational Application PCT/US2009/001688, filed Mar. 17, 2009, whichclaims the benefit of priority of U.S. Provisional Appl. No. 61/069,857,filed Mar. 18, 2008, U.S. Provisional Appl. No. 61/123,621, filed Apr.9, 2008, U.S. Provisional Appl. No. 61/207,220, filed Feb. 9, 2009, andU.S. Provisional Appl. No. 61/209,453, filed Mar. 6, 2009, each of whichis incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to certain compounds of Formula (Ia) andpharmaceutical compositions thereof that modulate the activity of thePGI2 receptor. Compounds of the present invention and pharmaceuticalcompositions thereof are directed to methods useful in the treatment of:pulmonary arterial hypertension (PAH); idiopathic PAH; familial PAH; PAHassociated with: a collagen vascular disease, a congenital heartdisease, portal hypertension, HIV infection, ingestion of a drug ortoxin, hereditary hemorrhagic telangiectasia, splenectomy, pulmonaryveno-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis(PCH); PAH with significant venous or capillary involvement; plateletaggregation; coronary artery disease; myocardial infarction; transientischemic attack; angina; stroke; ischemia-reperfusion injury;restenosis; atrial fibrillation; blood clot formation in an angioplastyor coronary bypass surgery individual or in an individual suffering fromatrial fibrillation; atherothmmbosis; asthma or a symptom thereof; adiabetic-related disorder such as diabetic peripheral neuropathy,diabetic nephropathy or diabetic retinopathy; glaucoma or other diseaseof the eye with abnormal intraocular pressure; hypertension;inflammation; psoriasis; psoriatic arthritis; rheumatoid arthritis;Crohn's disease; transplant rejection; multiple sclerosis; systemiclupus erythematosus (SLE); ulcerative colitis; atherosclerosis; acne;type 1 diabetes; type 2 diabetes; sepsis; and chronic obstructivepulmonary disorder (COPD).

BACKGROUND OF THE INVENTION

Prostacyclin (PGI2) is a lipid molecule derived from arachidonic acidthrough the cyclooxygenase pathway. It is a potent vasodilator,antiproliferative, anti-thrombotic and antiplatelet agent that mediatesits effects as an agonist of a G protein-coupled receptor (PGI2receptor, e.g., human PGI2 receptor. GenBank® Accession No. NP 000951and alleles thereof). It is known that the binding of PGI2 (or othersuch agonist) to the PGI2 receptor leads to coupling with the Gs proteinand increases intracellular cAMP levels. (See, e.g., Zhang et al., Arch.Biochem. Biophys., 2004 454:80 88.)

Pulmonary arterial hypertension (PAH) is a life-threatening diseasecharacterized by a progressive pulmonary vasculopathy leading to rightventricular hypertrophy. Right heart failure occurs if left untreated.Prostacyclin, which has vasodilatory and antiproliferative effects onthe pulmonary vasculature has been found to be low in patients with PAHcompared with normal controls. Exogenous administration of prostacyclinor an analog of prostacyclin (i.e., an agonist of the PGI2 receptor) hasbecome an important strategy in the treatment of PAH. (See, e.g., Tuderet al., Am. J. Respir. Crit. Care. Med., 1999, 159:1925-1932; Humbert etal., J. Am. Coll. Cardiol., 2004, 43:13S-24S; Rosenzweig, Expert Opin.Emerging Drugs, 2006, 11:609-619; McLaughlin et al., Circulation, 2006,114:1417-1431; Rosenkranz; Clin. Res. Cardiol., 2007, 96:527-541;Driscoll et al., Expert Opin. Pharmacother., 2008, 9:65-81.)

Trepostinil and iloprost are FDA-approved analogs of prostacyclin which,like prostacyclin, are not orally-active. Beraprost is an orally-activeanalog of prostacyclin approved for the treatment of PAH in Japan, butit has failed registration for the treatment of PAH in Europe and in theUS. Of the three FDA-approved drugs, prostacyclin is the best studied inPAH patients. The approximate annual cost of treating PAH with thesedrugs is $25,000 to $200,000 depending on the dose. At present, manyexperts consider intravenous prostacyclin to be the most reliable agentfor managing the sickest PAH patients. Due to the short half-life ofprostacyclin, intravenous treatment is complicated by the need for acontinuous infusion. Patients are at risk for potentially fatal reboundpulmonary hypertension if the infusion is abruptly disrupted, as well assignificant risk of catheter-related complications including sepsis.(See, e.g., Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11:609 619;Naeije et al., Expert Opin. Pharmacother., 2007, 8:2247-2265; Strauss etal., Clin. Chest. Med., 2007, 28:127-142; Driscoll et al., Expert Opin.Pharmacother., 2008, 9:65-81.)

There is considerable interest in developing prostacyclin analogs (i.e.,agonists of the PGI2 receptor) for use in the treatment of otherdiseases, such as atherothrombosis. Developing stable, orally-activeanalogs of prostacyclin (i.e., stable, orally-active agonists of thePGI2 receptor) is a rate-limiting step in achieving this goal (see,e.g., Arehart et al., Curr. Med. Chem., 2007, 14:2161-2169; Arehart etal., Circ. Res., 2008, Mar. 6 Epub ahead of print), as well as in theimproved management of PAH.

SUMMARY OF THE INVENTION

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula (Ia) and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen;

X is O or NR³; and

R³ is selected from H and C₁-C₆ alkyl.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula (XIIIa) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen;

X is O or NR³;

R³ is selected from H and C₁-C₆ alkyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H, 1-carboxyethylamino,1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropyiamino,1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino,4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino,carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino,1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,1-carboxy-2-phenylethylamino, 2-carboxypyrrdidin-1-yl,1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,1-carboxy-2-(1H-indol-3-yl)ethylamino,1-carboxy-2-(4-hydroxyphenyl)ethylamino and1-carboxy-2-methylpropylamino.

One aspect of the present invention pertains to methods of modulatingthe activity of a PGI2 receptor by contacting the receptor with acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods of agonizing aPGI2 receptor by contacting the receptor with a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of idiopathic PAH in an individual, comprising administeringto said individual in need thereof, a therapeutically effective amountof a compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of familial PAH in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a collagen vascular disease in anindividual, comprising administering to said individual in need thereof,a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a collagen vascular disease selectedfrom: scleroderma. CREST syndrome, systemic lupus erythematosus (SLE),rheumatoid arthritis, Takayasu's arteritis, polymyositis, anddermatomyositis in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a congenital heart disease in anindividual, comprising administering to said individual in need thereof,a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a congenital heart disease selectedfrom: atrial septic defect (ASD), ventricular septic defect (VSD) andpatent ductus arteriosus in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with portal hypertension in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with HIV infection in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with ingestion of a drug or toxin in anindividual, comprising administering to said individual in need thereof,a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with hereditary hemorrhagic telangiectasiain an individual, comprising administering to said individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with splenectomy in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound of the present inventionor a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with significant venous or capillaryinvolvement in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with pulmonary veno-occlusive disease (PVOD)in an individual, comprising administering to said individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with pulmonary capillary hemangiomatosis(PCH) in an individual, comprising administering to said individual inneed thereof, a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of platelet aggregation in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of: coronary artery disease, myocardial infarction, transientischemic attack angina, stroke, ischemia-reperfusion injury, restenosisor atrial fibrillation in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an angioplasty or coronary bypasssurgery individual comprising administering to said individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an individual suffering from atrialfibrillation comprising administering to said individual in needthereof, a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of atherosclerosis in an individual, comprising administeringto said individual in need thereof, a therapeutically effective amountof a compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of atherothrombosis in an individual, comprising administeringto said individual in need thereof, a therapeutically effective amountof a compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of asthma in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of a symptom of asthma in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of a diabetic-related disorder in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic peripheral neuropathy in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic nephropathy in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic retinopathy in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of glaucoma or other disease of the eye with abnormalintraocular pressure in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of hypertension in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of hypertension intended to confer protection against cerebralischemia in an individual, comprising administering to said individualin need thereof, a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of inflammation in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for thetreatment of an inflammatory disease in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of an inflammatory disease selected from: psoriasis, psoriaticarthritis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus (SLE), ulcerativecolitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne,type 1 diabetes, type 2 diabetes, sepsis, chronic obstructive pulmonarydisorder (COPD) and asthma in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a PGI2 receptor mediated disorder.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of idiopathic PAH.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of familial PAH.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with vascular collagen disease.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with a collagen vascular disease selectedfrom: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE),rheumatoid arthritis, Takayasu's arteritis, polymyositis, anddermatomyositis.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with a congenital heart disease.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with a congenital heart disease selectedfrom: atrial septic defect (ASD), ventricular septic defect (VSD) andpatent ductus arteriosus.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with portal hypertension.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with HIV infection.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with ingestion of a drug or toxin.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with hereditary hemorrhagic telangiectasia.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with splenectomy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with significant venous or capillaryinvolvement.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with pulmonary veno-occlusive disease(PVOD).

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of PAH associated with pulmonary capillary hemangiomatosis(PCH).

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of platelet aggregation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a PGI2 receptor mediated disorder selected from: coronaryartery disease, myocardial infarction, transient ischemic attack,angina, stroke, ischemia-reperfusion injury, restenosis and atrialfibrillation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of blood clot formation in an angioplasty or coronary bypasssurgery individual.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of blood clot formation in an individual suffering from atrialfibrillation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of atherosclerosis.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of atherothrombosis.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of asthma.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a symptom of asthma.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of a diabetic-related disorder.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of diabetic peripheral neuropathy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of diabetic nephropathy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of diabetic retinopathy.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of glaucoma or other disease of the eye with abnormalintraocular pressure.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of hypertension.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of hypertension intended to confer protection against cerebralischemia.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of inflammation.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of an inflammatory disease.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment of an inflammatory disease selected from: psoriasis, psoriaticarthritis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus (SLE), ulcerativecolitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne,type 1 diabetes, type 2 diabetes, sepsis, chronic obstructive pulmonarydisorder (COPD) and asthma.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for modulatingthe activity of a PGI2 receptor.

One aspect of the present invention pertains to the use of a compound ofthe present invention in the manufacture of a medicament for agonizing aPGI2 receptor.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of the human or animal bodyby therapy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a PGI2 receptor mediateddisorder.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of idiopathic PAH.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of familial PAH.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acollagen vascular disease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acollagen vascular disease selected from: scleroderma CREST syndrome,systemic lupus erythematosus (SLE), rheumatoid arthritis. Takayasu'sarteritis, polymyositis, and dermatomyositis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acongenital heart disease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with acongenital heart disease selected from: atrial septic defect (ASD),ventricular septic defect (VSD) and patent ductus arteriosus.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with portalhypertension.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated with HIVinfection.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withingestion of a drug or toxin.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withhereditary hemorrhagic telangiectasia.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withsplenectomy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withsignificant venous or capillary involvement.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withpulmonary veno-occlusive disease (PVOD).

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of PAH associated withpulmonary capillary hemangiomatosis (PCH).

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of platelet aggregation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of: coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke,ischemia-reperfusion injury, restenosis or atrial fibrillation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of blood clot formationin an angioplasty or coronary bypass surgery individual.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of blood clot formationin an individual suffering from atrial fibrillation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of atherosclerosis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of atherothrombosis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of asthma.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a symptom of asthma.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a diabetic-relatedcomplication.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of a diabetic-relateddisorder.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of diabetic nephropathy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of diabetic retinopathy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of glaucoma or other diseaseof the eye with abnormal intraocular pressure.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of glaucoma or other diseaseof the eye with abnormal intraocular pressure.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of hypertension.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of hypertension intended toconfer protection against cerebral ischemia.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of inflammation.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of an inflammatory disease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of treatment of an inflammatory diseaseselected from: psoriasis, psoriatic arthritis, rheumatoid arthritis,Crohn's disease, transplant rejection, multiple sclerosis, systemiclupus erythematosus (SLE), ulcerative colitis, ischemia-reperfusioninjury, restenosis, atherosclerosis, acne, type 1 diabetes, type 2diabetes, sepsis, chronic obstructive pulmonary disorder (COPD) andasthma.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of modulating the activity of a PGI2receptor.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method of agonizing a PGI2 receptor.

One aspect of the present invention pertains to processes for preparinga composition comprising admixing a compound of the present inventionand a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to pharmaceuticalcompositions comprising a compound, salt, hydrate, solvate orcrystalline form of the present invention and a pharmaceuticallyacceptable carrier.

One aspect of the present invention pertains to methods of modulatingthe activity of a PGI2 receptor by contacting the receptor with acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods of agonizing aPGI2 receptor by contacting the receptor with a compound, salt, hydrate,solvate or crystalline form of the present invention or a pharmaceuticalcomposition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of idiopathic PAH in an individual, comprising administeringto said individual in need thereof, a therapeutically effective amountof a compound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of familial PAH in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a collagen vascular disease in anindividual, comprising administering to said individual in need thereof,a therapeutically effective amount of a compound, salt, hydrate, solvateor crystalline form of the present invention or a pharmaceuticalcomposition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a collagen vascular disease selectedfrom: scleroderma. CREST syndrome, systemic lupus erythematosus (SLE),rheumatoid arthritis, Takayasu's arteritis, polymyositis, anddermatomyositis in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a congenital heart disease in anindividual, comprising administering to said individual in need thereof,a therapeutically effective amount of a compound, salt, hydrate, solvateor crystalline form of the present invention or a pharmaceuticalcomposition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with a congenital heart disease selectedfrom: atrial septic defect (ASD), ventricular septic defect (VSD) andpatent ductus arteriosus in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with portal hypertension in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound, salt, hydrate, solvateor crystalline form of the present invention or a pharmaceuticalcomposition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with HIV infection in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound, salt, hydrate, solvateor crystalline form of the present invention or a pharmaceuticalcomposition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with ingestion of a drug or toxin in anindividual, comprising administering to said individual in need thereof,a therapeutically effective amount of a compound, salt, hydrate, solvateor crystalline form of the present invention or a pharmaceuticalcomposition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with hereditary hemorrhagic telangiectasiain an individual, comprising administering to said individual in needthereof, a therapeutically effective amount of a compound, salt,hydrate, solvate or crystalline form of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with splenectomy in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound, salt, hydrate, solvateor crystalline form of the present invention or a pharmaceuticalcomposition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with significant venous or capillaryinvolvement in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with pulmonary veno-occlusive disease (PVOD)in an individual, comprising administering to said individual in needthereof, a therapeutically effective amount of a compound, salt,hydrate, solvate or crystalline form of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH associated with pulmonary capillary hemangiomatosis(PCH) in an individual, comprising administering to said individual inneed thereof, a therapeutically effective amount of a compound, salt,hydrate, solvate or crystalline form of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of platelet aggregation in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound, salt, hydrate, solvate or crystallineform of the present invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of: coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke, ischemia-reperfusion injury, restenosisor atrial fibrillation in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an angioplasty or coronary bypasssurgery individual comprising administering to said individual in needthereof, a therapeutically effective amount of a compound, salt,hydrate, solvate or crystalline form of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an individual suffering from atrialfibrillation comprising administering to said individual in needthereof, a therapeutically effective amount of a compound, salt,hydrate, solvate or crystalline form of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of atherosclerosis in an individual, comprising administeringto said individual in need thereof, a therapeutically effective amountof a compound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of atherothrombosis in an individual, comprising administeringto said individual in need thereof, a therapeutically effective amountof a compound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of asthma in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of a symptom of asthma in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound, salt, hydrate, solvate or crystallineform of the present invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of a diabetic-related disorder in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound, salt, hydrate, solvate or crystallineform of the present invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic peripheral neuropathy in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound, salt, hydrate, solvate or crystallineform of the present invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic nephropathy in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound, salt, hydrate, solvate or crystallineform of the present invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of diabetic retinopathy in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound, salt, hydrate, solvate or crystallineform of the present invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of glaucoma or other disease of the eye with abnormalintraocular pressure in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of hypertension in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of hypertension intended to confer protection against cerebralischemia in an individual, comprising administering to said individualin need thereof, a therapeutically effective amount of a compound, salt,hydrate, solvate or crystalline form of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of inflammation in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of an inflammatory disease in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound, salt, hydrate, solvate or crystallineform of the present invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of an inflammatory disease selected from: psoriasis, psoriaticarthritis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus (SLE), ulcerativecolitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne,type 1 diabetes, type 2 diabetes, sepsis, chronic obstructive pulmonarydisorder (COPD) and asthma in an individual, comprising administering tosaid individual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of a PGI2 receptor mediated disorder in an individual,comprising administering to said individual in need thereof, atherapeutically effective amount of a compound, salt, hydrate, solvateor crystalline form of the present invention or a pharmaceuticalcomposition thereof.

One aspect of the present invention pertains to methods for thetreatment of PAH selected from: idiopathic PAH; familial PAH; PAHassociated with a collagen vascular disease selected from: scleroderma,CREST syndrome, systemic lupus erythematosus (SLE), rheumatoidarthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; PAHassociated with a congenital heart disease selected from: atrial septicdefect (ASD), ventricular septic defect (VSD) and patent ductusarteriosus in an individual; PAH associated with portal hypertension;PAH associated with HIV infection; PAH associated with ingestion of adrug or toxin; PAH associated with hereditary hemorrhagictelangiectasia; PAH associated with splenectomy; PAH associated withsignificant venous or capillary involvement; PAH associated withpulmonary verso-occlusive disease (PVOD); and PAH associated withpulmonary capillary hemangiomatosis (PCH) in an individual, comprisingadministering to said individual in need thereof, a therapeuticallyeffective amount of a compound, salt, hydrate, solvate or crystallineform of the present invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for thetreatment of a disorder selected from: platelet aggregation, coronaryartery disease, myocardial infarction, transient ischemic attack,angina, stroke, ischemia-reperfusion injury, restenosis, atrialfibrillation, blood clot formation, atherosclerosis, atherothrombosis,asthma, a symptom of asthma, a diabetic-related disorder, diabeticperipheral neuropathy, diabetic nephropathy, diabetic retinopathy,glaucoma or other disease of the eye with abnormal intraocular pressure,hypertension, inflammation, psoriasis, psoriatic arthritis, rheumatoidarthritis, Crohn's disease, transplant rejection, multiple sclerosis,systemic lupus erythematosus (SLE), ulcerative colitis,ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1diabetes, type 2 diabetes, sepsis and chronic obstructive pulmonarydisorder (COPD) in an individual, comprising administering to saidindividual in need thereof, a therapeutically effective amount of acompound, salt, hydrate, solvate or crystalline form of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of a PGI2 receptormediated disorder.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of idiopathic PAH.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of familial PAH.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate a crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated withvascular collagen disease.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated witha collagen vascular disease selected from: scleroderma, CREST syndrome,systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu'sarteritis, polymyositis, and dermatomyositis.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated witha congenital heart disease.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate cc crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated witha congenital heart disease selected from: atrial septic defect (ASD),ventricular septic defect (VSD) and patent ductus arteriosus.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate cc crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated withportal hypertension.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated withHIV infection.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate a crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated withingestion of a drug or toxin.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate a crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated withhereditary hemorrhagic telangiectasia.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated withsplenectomy.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated withsignificant venous or capillary involvement.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated withpulmonary veno-occlusive disease (PVOD).

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate a crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH associated withpulmonary capillary hemangiomatosis (PCH).

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of plateletaggregation.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of a PGI2 receptormediated disorder selected from: coronary artery disease, myocardialinfarction, transient ischemic attack, angina, stroke,ischemia-reperfusion injury, restenosis and atrial fibrillation.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of blood clotformation in an angioplasty or coronary bypass surgery individual.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of blood clotformation in an individual suffering from atrial fibrillation.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate cc crystalline form of the present invention, inthe manufacture of a medicament for the treatment of atherosclerosis.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate cc crystalline form of the present invention, inthe manufacture of a medicament for the treatment of atherothrombosis.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of asthma.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate cc crystalline form of the present invention, inthe manufacture of a medicament for the treatment of a symptom ofasthma.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of a diabetic-relateddisorder.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of diabetic peripheralneuropathy.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate cc crystalline form of the present invention, inthe manufacture of a medicament for the treatment of diabeticnephropathy.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of diabeticretinopathy.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of glaucoma or otherdisease of the eye with abnormal intraocular pressure.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate cc crystalline form of the present invention, inthe manufacture of a medicament for the treatment of hypertension.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of hypertensionintended to confer protection against cerebral ischemia.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate cc crystalline form of the present invention, inthe manufacture of a medicament for the treatment of inflammation.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate cc crystalline form of the present invention, inthe manufacture of a medicament for the treatment of an inflammatorydisease.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of an inflammatorydisease selected from: psoriasis, psoriatic arthritis, rheumatoidarthritis, Crohn's disease; transplant rejection, multiple sclerosis,systemic lupus erythematosus (SLE), ulcerative colitis,ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type Idiabetes, type 2 diabetes, sepsis, chronic obstructive pulmonarydisorder (COPD) and asthma.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for modulating the activity of a PGI2receptor.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for agonizing a PGI2 receptor.

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of PAH selected from:idiopathic PAH; familial PAH; PAH associated with a collagen vasculardisease selected from: scleroderma, CREST syndrome, systemic lupuserythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis,polymyositis, and dermatomyositis; PAH associated with a congenitalheart disease selected from: atrial septic defect (ASD), ventricularseptic defect (VSD) and patent ductus arteriosus in an individual; PAHassociated with portal hypertension; PAH associated with HIV infection;PAH associated with ingestion of a drug or toxin; PAH associated withhereditary hemorrhagic telangiectasia; PAH associated with splenectomy;PAH associated with significant venous or capillary involvement; PAHassociated with pulmonary verso-occlusive disease (PVOD); and PAHassociated with pulmonary capillary hemangiomatosis (PCH).

One aspect of the present invention pertains to the use of a compound,salt, hydrate, solvate or crystalline form of the present invention, inthe manufacture of a medicament for the treatment of a disorder selectedfrom: platelet aggregation, coronary artery disease, myocardialinfarction, transient ischemic attack, angina, stroke,ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clotformation, atherosclerosis, atherothrombosis, asthma, a symptom ofasthma, a diabetic-related disorder, diabetic peripheral neuropathy,diabetic nephropathy, diabetic retinopathy, glaucoma or other disease ofthe eye with abnormal intraocular pressure, hypertension, inflammation,psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease,transplant rejection, multiple sclerosis, systemic lupus erythematosus(SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis,atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis andchronic obstructive pulmonary disorder (COPD).

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of the human or animal body by therapy.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of a PGI2 receptor mediated disorder.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of idiopathic PAH.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of familial PAH.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with a collagen vasculardisease.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with a collagen vascular diseaseselected from: scleroderma, CREST syndrome, systemic lupus erythematosus(SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, anddermatomyositis.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with a congenital heart disease.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with a congenital heart diseaseselected from: atrial septic defect (ASD), ventricular septic defect(VSD) and patent ductus arteriosus.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with portal hypertension.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with HIV infection.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with ingestion of a drug ortoxin.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with hereditary hemorrhagictelangiectasia.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with splenectomy.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with significant venous orcapillary involvement.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with pulmonary veno-occlusivedisease (PVOD).

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of PAH associated with pulmonary capillaryhemangiomatosis (PCH).

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of platelet aggregation.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of: coronary artery disease, myocardialinfarction, transient ischemic attack, angina, stroke,ischemia-reperfusion injury, restenosis or atrial fibrillation.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method for the treatment of blood clot formation in an angioplasty orcoronary, bypass surgery individual.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method for the treatment of blood clot formation in an individualsuffering from atrial fibrillation.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of atherosclerosis.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of atherothrombosis.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of asthma.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of a symptom of asthma.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of a diabetic-related complication.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of a diabetic-related disorder.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of diabetic peripheral neuropathy.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of diabetic nephropathy.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of glaucoma or other disease of the eye withabnormal intraocular pressure.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of hypertension.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of hypertension intended to confer protectionagainst cerebral ischemia.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of inflammation.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of an inflammatory disease.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of treatment of an inflammatory disease selected from:psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease,transplant rejection, multiple sclerosis, systemic lupus erythematosus(SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis,atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis, chronicobstructive pulmonary disorder (COPD) and asthma.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of modulating the activity of a PGI2 receptor.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate or crystalline form of the present invention for use ina method of agonizing a PGI2 receptor.

One aspect of the present invention pertains to a compound, salt,hydrate, solvate, crystalline form or pharmaceutical composition of thepresent invention for use in a method of treatment of PAH selected from:idiopathic PAH; familial PAH; PAH associated with a collagen vasculardisease selected from: scleroderma, CREST syndrome, systemic lupuserythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis,polymyositis, and dermatomyositis; PAH associated with a congenitalheart disease selected from: atrial septic defect (ASD), ventricularseptic defect (VSD) and patent ductus arteriosus in an individual; PAHassociated with portal hypertension; PAH associated with HIV infection;PAH associated with ingestion of a drug or toxin; PAH associated withhereditary hemorrhagic telangiectasia; PAH associated with splenectomy;PAH associated with significant venous or capillary involvement; PAHassociated with pulmonary verso-occlusive disease (PVOD); and PAHassociated with pulmonary capillary hemangiomatosis (PCH).

One aspect of the present invention pertains to a compound, salt,hydrate, solvate, crystalline form or pharmaceutical composition of thepresent invention for use in a method of treatment of a disorderselected from: platelet aggregation, coronary artery disease, myocardialinfarction, transient ischemic attack, angina, stroke,ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clotformation, atherosclerosis, atherothrombosis, asthma, a symptom ofasthma a diabetic-related disorder, diabetic peripheral neuropathy,diabetic nephropathy, diabetic retinopathy, glaucoma or other disease ofthe eye with abnormal intraocular pressure, hypertension, inflammation,psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease,transplant rejection, multiple sclerosis, systemic lupus erythematosus(SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis,atherosclerosis, acne, type 1 diabetes, type 2 diabetes, sepsis andchronic obstructive pulmonary disorder (COPD).

One aspect of the present invention pertains to processes for preparinga composition comprising admixing a compound, salt, hydrate, solvate orcrystalline form of the present invention, and a pharmaceuticallyacceptable carrier.

The present invention further provides, interalia, processes forpreparing compounds of Formula (II):

or a salt, solvate or hydrate thereof;wherein:

R¹ is selected from C₁-C₆ alkyl, aryl and heteroaryl; each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R² is selected from: H, C₁-C₆ alkyl and aryl; wherein said aryl isoptionally substituted with one or two substituents selected from: C₁-C₆alkyl and halogen;

comprising reacting a compound of Formula (III):

or a salt form thereof;wherein:

R⁵ is C₁-C₆ alkyl;

with a hydrolyzing agent to form a compound of Formula (II) or a salt,solvate or hydrate thereof.

The present invention further provides processes for preparing compoundsof Formula (III):

or a salt form thereof;wherein:

R¹ is selected from C₁-C₆ alkyl, aryl and heteroaryl; each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R² is selected from: H, C₁-C₆ alkyl and aryl; wherein said aryl isoptionally substituted with one or two substituents selected from: C₁-C₆alkyl and halogen; and

R⁵ is C₁-C₆ alkyl;

comprising reacting a compound of Formula (IV):

or a salt form thereof;with a compound of Formula (V):

wherein:

R⁶ is selected from: C₁-C₆ alkylarylsulfonate, C₁-C₆ alkylsulfonate,arylsulfonate, C₁-C₆ haloalkylsulfonate and halogen;

in the presence of a base to form a compound of Formula (III) or a saltform thereof.

The present invention further provides processes for preparing compoundsof Formula (IV):

or a salt form thereof:wherein:

R¹ is selected from C₁-C₆ alkyl, aryl and heteroaryl; each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R² is selected from: H, C₁-C₆ alkyl and aryl; wherein said aryl isoptionally substituted with one or two substituents selected from: C₁-C₆alkyl and halogen;

comprising reacting a compound of Formula (VI):

or a salt form thereof;wherein:

R⁷ is a first leaving group:

with a compound of formula (VII):

to form a compound of Formula (IV) or a salt form thereof.

The present invention further provides processes for preparing compoundsof Formula (VI):

or a salt form thereof;wherein:

R¹ is selected from C₁-C₆ alkyl, aryl and heteroaryl; each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R² is selected from: H, C₁-C₆ alkyl and aryl; wherein said aryl isoptionally substituted with one or two substituents selected from: C₁-C₆alkyl and halogen; and

R⁷ is a first leaving group;

comprising reacting a compound of Formula (VIII):

or a salt form thereof;with a compound of formula (IX):

wherein:

R⁸ is a second leaving group;

to form a compound of Formula (VI) or a salt form thereof.

The present invention further provides processes for preparing salts ofcompounds of Formula (II):

comprising reacting a compound of Formula (II) with a salt-formingreagent to form a salt of a compound of formula (H).

The present invention further provides salts of compounds of Formula(II) prepared by the processes described herein.

The present invention further provides pharmaceutical compositions ofcompounds of Formula (II) prepared by the processes described herein.

The present invention further provides compounds of Formula (III) andFormula (IV) prepared by the processes described herein.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows two general methods for preparing an intermediate useful inthe synthesis of compounds of the present invention.Cyclohexane-1,4-dicarboxylic acid may be converted to the correspondingdiol either directly, or via an ester, by reduction with lithiumaluminium hydride. Reaction of the diol, with tert-butyldiazoacetate inthe presence of a rhodium catalyst affords a 2-tert-butoxy-2-oxoethoxyderivative which may be converted to an amine via the azide.

FIG. 2 shows a general method of preparing compounds of the presentinvention. An isocyanate is coupled to cyclohexane-1,4-diyldimethanol inthe presence of pyridine to form a carbamate. This is converted to a2-tert-butoxy-2-oxoethoxy derivative with tert-butyldiazoacetate in thepresence of a rhodium catalyst and the carbamate is alkylated with ahalide derivative. Finally the ester is hydrolyzed to leave a compoundof Formula (Ia).

FIG. 3 shows general methods of preparing compounds of the presentinvention. First, a halide derivative is reacted with an amine in thepresence of a palladium catalyst to form a secondary amine. This isreacted with triphosgene to form a chlorocarbonylamine which is reactedwith a cyclohexane derivative to form an alcohol. Next, the alcohol isconverted in one pot via the 2-tert-butoxy-2-oxoethoxy derivative to acompound of Formula (Ia) by reaction with tert-butyldiazoacetate in thepresence of a rhodium catalyst, followed by acidic hydrolysis.Alternatively, a compound of Formula (Ia) may be prepared by reaction ofthe chlorocarbonylamine with a 2-tert-butoxy-2-oxoethoxycyclohexanederivative in pyridine followed by acidic hydrolysis. A compound ofFormula (Ia) may be converted to the corresponding sodium salt bytreatment with sodium methoxide.

FIG. 4 shows general methods for preparing compounds of Formula (Ia). Inone method a chlorocarbonylamine is reacted with tert-butyl2-((4-(aminomethyl)cyclohexyl)methoxy)acetate in the presence of a baseand the product is hydrolyzed. In another method a chlorocarbonylamineis reacted with 2-((4-(aminomethyl)cyclohexyl)methoxy)acetic acid in thepresence of a base. In another method a secondary amine is reacted with2-((4-(aminomethyl)cyclohexyl)methyl)acetate in the presence oftriphosgene.

FIG. 5 shows method for preparing intermediates useful in the synthesisof compounds of the present invention, tert-Butyl(4-(hydroxymethyl)cyclohexyl)methylcarbamate can be reacted withbromoacetic acid to form tert-butyl2-((4-((tert-butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate. Theresulting intermediate may be hydrolyzed with HCl at room temperature togive tert-butyl 2-((4-(aminomethyl)cyclohexyl)methoxy)acetate, orhydrolyzed with HCl at 60° C. to give2-((4-(aminomethyl)cyclohexyl)methoxy)acetic acid.

FIG. 6 shows a general method of preparing compounds of the presentinvention, tert-Butyl (4-(hydroxymethyl)cyclohexyl)methylcarbamate isalkylated with ethyl 2-diazoacetate in the presence of a rhodiumcatalyst to give ethyl2-((4-((tert-butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate whichmay be hydrolyzed to the free amine by treatment with HCl at roomtemperature. This is reacted with disuccinimidyl carbonate and then asecondary amine to give a urea Finally the ester is hydrolyzed with HClat 60° C. to afford a compound of Formula (Ia).

FIG. 7 shows the results of an experiment which measured the ability ofCompound 23 to inhibit the right ventricle hypertrophic response toMCT-induced pulmonary arterial hypertension in rat.

FIG. 8 shows the results of an experiment which measured the ability ofCompound 22 to inhibit the right ventricle hypertrophic response toMCT-induced pulmonary arterial hypertension in rat.

FIG. 9 depicts a powder X-ray diffraction pattern (PXRD) for a samplecontaining a crystalline form (Form 1) of sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate(the sodium salt of Compound 22) (PANalytical X'Pert Plus Powder X-RayDiffractometer; 5.0 to 40.0°24.

FIG. 10 depicts a dynamic vapor sorption (DVS) profile for Form 1 of thesodium salt of Compound 22 (VTI dynamic vapor sorption analyzer).

FIG. 11 depicts a differential scanning calorimetry (DSC) thermogram forForm 1 of the sodium salt of Compound 22 (TA Instruments DSC Q1000; 10°C./min). FIG. 11 also depicts a thermogravimetric analysis (TGA)thermogram fa Form 1 of the sodium salt of Compound 22 (TA InstrumentsTGA Q500 in open cell; 10° C./min).

FIG. 12 depicts a thermogravimetric analysis (TGA) thermogram for ahydrate of the sodium salt of Compound 22.

FIG. 13 depicts a powder X-ray diffraction pattern (PXRD) for a samplecontaining a hydrate of the sodium salt of Compound 22.

FIG. 14 depicts a thermogravimetric analysis (TGA) thermogram for ahydrate of the sodium salt of Compound 23.

FIG. 15 depicts a powder X-ray diffraction pattern (PXRD) for a samplecontaining a hydrate of the sodium salt of Compound 23.

FIG. 16 depicts a thermogravimetric analysis (TGA) thermogram for asolvate of the magnesium salt of Compound 23.

FIG. 17 depicts a powder X-ray diffraction pattern (PXRD) for a samplecontaining a solvate of the magnesium salt of Compound 23.

FIG. 18 depicts a thermogravimetric analysis (TGA) thermogram for asolvate of the potassium salt of Compound 23.

FIG. 19 depicts a powder X-ray diffraction pattern (PXRD) for a samplecontaining a solvate of the potassium salt of Compound 23.

FIG. 20 depicts a thermogravimetric analysis (TGA) thermogram for asolvate of the calcium salt of Compound 23.

FIG. 21 depicts a powder X-ray diffraction pattern (PXRD) for a samplecontaining a solvate of the calcium salt of Compound 23.

FIG. 22 depicts the MS (top) and MS/MS (bottom) spectra of the taurineconjugate of Compound 22 (Compound 99).

FIG. 23 depicts the MS (top) and MS/MS (bottom) spectra of the glycineconjugate of Compound 22 (Compound 100).

FIG. 24 shows the mean plasma concentration-time profiles of Compound 22and Compound 22 taurine conjugate (Compound 99) after a 1.25 mg/kg oraldose of Compound 22 taurine conjugate to male rats.

FIG. 25 shows the mean plasma concentration-time profile of Compound 22after a 10 mg/kg oral dose of Compound 22 sodium salt to male rats.

FIG. 26 depicts a differential scanning calorimetry (DSC) thermogram forthe crystalline form of Compound 22 of the present invention (TAInstruments DSC Q1000; 10° C./min). FIG. 26 also depicts athermogravimetric analysis (TGA) thermogram for the crystalline form ofCompound 22 of the present invention (TA Instruments TGA Q500 in opencell; 10° C./min).

FIG. 27 depicts a powder X-ray diffraction pattern (PXRD) for a samplecontaining the crystalline form of Compound 22 of the present invention(PANalytical X'Pert Plus Powder X-Ray Diffractometer: 5.0 to 40.0°2θ.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “agonists” is intended to mean moieties that interact andactivate the receptor, such as, the PGI2 receptor and initiate aphysiological or pharmacological response characteristic of thatreceptor. For example, when moieties activate the intracellular responseupon binding to the receptor, or enhance GTP binding to membranes.

The term “contact or contacting” is intended to mean bringing theindicated moieties together, whether in an in vitro system or an in vivosystem. Thus, “contacting” a PGI2 receptor with a compound of theinvention includes the administration of a compound of the presentinvention to an individual, preferably a human, having a PGI2 receptor,as well as, for example, introducing a compound of the invention into asample containing a cellular or more purified preparation containing aPGI2 receptor.

The term “hydrate” as used herein means a compound of the invention or asalt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The term “in need of treatment” and the term “in need thereof,” whenreferring to treatment are used interchangeably to mean a judgment madeby a caregiver (e.g. physician, nurse, nurse practitioner, etc. in thecase of humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsof the invention. Accordingly, the compounds of the invention can beused in a protective or preventive manner; or compounds of the inventioncan be used to alleviate, inhibit or ameliorate the disease, conditionor disorder.

The term “individual” is intended to mean any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates and most preferably humans.

The term “modulate or modulating” is intended to mean an increase ordecrease in the amount, quality, response or effect of a particularactivity, function or molecule.

The term “pharmaceutical composition” is intended to mean a compositioncomprising at least one active ingredient; including but not limited to,salts, solvates and hydrates of compounds of the present invention;whereby the composition is amenable to investigation fora specified,efficacious outcome in a mammal (for example, without limitation, ahuman). Those of ordinary skill in the art will understand andappreciate the techniques appropriate for determining whether an activeingredient has a desired efficacious outcome based upon the needs of theartisan.

The term “solvate” as used herein means a compound of the invention or asalt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

The term “therapeutically effective amount” is intended to mean theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician or caregiver; or in an individual, whichincludes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease,

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease,

condition or disorder (i.e., arresting further development of thepathology and/or symptomatology) and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The term “reacting” is used herein as known in the art and generallyrefers to the bringing together of chemical reagents in such a manner soas to allow their interaction at the molecular level to achieve achemical or physical transformation of at least one chemical reagent.

Chemical Group, Moiety or Radical

The term “C₁-C₆ aryl” is intended to mean a C₁-C₆ alkyl radical attachedto the carbon of a carbonyl group wherein the definition of alkyl hasthe same definition as described herein; some examples include, but arenot limited to, acetyl, propionyl, n-butanoyl, sec-butanoyl, pivaloyl,pentanoyl and the like.

The term “C₁-C₆ alkoxy” is intended to mean a C₁-C₆ alkyl radical, asdefined herein, attached directly to an oxygen atom. The embodiments are1 to 5 carbons; some embodiments are 1 to 4 carbons; some embodimentsare 1 to 3 carbons; and some embodiments are 1 or 2 carbons. Examplesinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy,isobutoxy, sec-butoxy and the like.

The term “C₁-C₆ alkyl” is intended to mean a straight or branched carbonradical containing 1 to 6 carbons. The embodiments are 1 to 5 carbons.The embodiments are 1 to 4 carbons. The embodiments are 1 to 3 carbons.The embodiments are 1 or 2 carbons. The embodiments are 1 carbonExamples of an alkyl include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl,isopentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,—CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl andthe like.

The term “C₁-C₆ alkylamino” is intended to mean one alkyl radicalattached to a NH radical wherein the alkyl radical has the same meaningas described herein. The examples include, but not limited to,methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino,sec-butylamino, isobutylamino, t-butylamino, and the like. Theembodiments are “C₁-C₂ alkylamino.”

The term “C₁-C₆ alkylcarboxamido” or “C₁-C₆ alkylcarboxamide” isintended to mean one C₁-C₆ alkyl group attached to either the carbon orthe nitrogen of an amide group, wherein alkyl has the same definition asfound herein. The C₁-C₆ alkylcarboxamido may be represented by thefollowing:

Examples include, but are not limited to, N-methylcarboxamide,N-ethylcarboxamide, N-n-propylcarboxamide, N-isopropylcarboxamide,N-n-butylcarboxamide, N-sec-butylcarboxamide, N-isobutylcarboxamide,N-t-butylcarboxamide and the like.

The term “C₁-C₆ alkylsulfanyl” is intended to mean a C₁-C₆ alkyl radicalattached to a sulfur atom (i.e., S) wherein the alkyl radical has thesame definition as described herein. Examples include, but are notlimited to, methylsulfanyl (i.e., CH₃S—), ethylsulfanyl,n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,isobutylsulfanyl, t-butylsulfanyl, and the like.

The term “C₁-C₆ alkylsulfinyl” is intended to mean a C₁-C₆ alkyl radicalattached to the sulfur of a sulfoxide radical having the formula: —S(O)—wherein the alkyl radical has the same definition as described herein.Examples include, but are not limited to, methylsulfinyl, ethylsulfiny1, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl,sec-butylsulfinyl, isobutylsulfinyl, t-butylsulfinyl, and the like.

The term “C₁-C₆ alkylsulfonamide” is intended to mean the groups shownbelow:

wherein C₁-C₆ alkyl has the same definition as described herein.

The term “C₁-C₆ alkylsulfonyl” is intended to mean a C₁-C₆ alkyl radicalattached to the sulfur of a sulfone radical having the formula: —S(O)₂—wherein the alkyl radical has the same definition as described herein.Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,isobutylsulfonyl, t butylsulfonyl, and the like.

The term “amino” is intended to mean the group —NH₂.

The term “aryl” is intended to mean an aromatic ring radical containing6 to 10 ring carbons. Examples include phenyl and naphthyl.

The term “carbo-C₁-C₆-alkoxy” is intended to mean a C₁-C₆ alkyl ester ofa carboxylic acid, wherein the alkyl group is as defined herein.Examples include, but are not limited to, carbomethoxy [—C(═O)OCH₃],carbo-ethoxy, carbo-propoxy, carbo-isopropoxy, carbo-butoxy, carbosec-butoxy, carbo-isobutoxy, carbo-t-butoxy, carbo-n-pentoxy,carbo-isopentoxy, carbo-t-pentoxy, carbo-neo-pentoxy, carbo-n-hexyloxy,and the like.

The term “carboxamide” is intended to mean the group —CONH₂.

The term “carboxy” or “carboxyl” is intended to mean the group —CO₂H,also referred to as a carboxylic acid group.

The term “cyano” is intended to mean the group —CN.

The term “C₂-C₈ dialkylamino” is intended to mean an amino substitutedwith two of the same or different C₁-C₄ alkyl radicals wherein alkylradical has the same definition as described herein. The examplesinclude, but are not limited to, dimethylamino, methylethylamino,diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino,ethylisopropylamino, dipropylamino, propylisopropylamino and the like.The embodiments are “C₂-C₄ dialkylamino.”

The term “C₂-C₈ dialkylcarboxamido” or “C₂-C₈ dialkykarboxamide” isintended to mean two alkyl radicals, that are the same or different,attached to an amide group, wherein alkyl has the same definition asdescribed herein. A C₂-C₈ dialkylcarboxamido may be represented by thefollowing groups:

wherein C₁-C₄ has the same definition as described herein. Examples of adialkylcarboxamide include, but are not limited to,N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide,N,N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.

The term “C₂-C₈ dialkylsulfonanide” is intended to mean one of thefollowing groups shown below:

wherein C₁-C₄ has the same definition as described herein, for examplebut not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.

The term “guanidino” is intended to mean —NHC(═NH)NH₂.

The term “halogen” or “halo” is intended to mean to a fluoro, chloro,bromo or iodo group.

The term “C₁-C₆ haloalkoxy” is intended to mean a C₁-C₄ haloalkyl, asdefined herein, which is directly attached to an oxygen atom. Examplesinclude, but are not limited to, difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.

The term “C₁-C₆ haloalkyl” is intended to mean a C₁-C₆ alkyl group,defined herein, wherein the alkyl is substituted with one halogen up tofully substituted and a fully substituted C₁-C₆ haloalkyl can berepresented by the formula C_(n)L_(2n+1) wherein L is a halogen and “n”is 1, 2, 3, 4, 5 or 6; when more than one halogen is present then theymay be the same or different and selected from the group consisting ofF, Cl, Br and I, preferably F, some embodiments are 1 to 5 carbons, someembodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, andsome embodiments are 1 or 2 carbons. Examples of haloalkyl groupsinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl and the like.

The term “heteroaryl” is intended to mean an aromatic ring systemcontaining 5 to 14 aromatic ring atoms that may be a single ring, twofused rings or three fused rings wherein at least one aromatic ring atomis a heteroatom selected from, but not limited to, the group consistingof 0, S and N wherein the N can be optionally substituted with H, C₁-C₄acyl or C₁-C₄ alkyl. The embodiments contain 5 to 6 ring atoms forexample furanyl, thienyl, pyridyl, imidazolyl, oxazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyland the like. The embodiments contain 8 to 14 ring atoms for examplecarbazolyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl,isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl,benzothienyl, benzofuranyl, isobenzofuran and the like.

The term “heterocyclic” or “heterocyclyl” is intended to mean a ringsystem containing 3 to ring atoms that may be a single ring, two fusedrings or three fused rings, wherein at least one ring atom is aheteroatom or substituted heteroatom selected from, but not limited to,the group consisting of O, S, S(═O), S(═O)₂ and NH, wherein the N isoptionally substituted with C₁-C₄ acyl or C₁-C₄ alkyl. In someembodiments, the ring carbon atoms are optionally substituted with oxothus forming a carbonyl group. In some embodiments the heterocyclicgroup is a 3-, 4-, 5-, 6- or 7-membered ring. In some embodiments theheterocyclic group is a bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. In some embodiments theheterocyclic group is a tricyclic group in which any of theabove-defined heterocyclic rings is fused to two benzene rings. Examplesof a heterocyclic group include, but are not limited to,[1,3]-dioxolanyl, [1,4]-dioxanyl, [1,4]-oxazepanyl,10,11-dihydro-5H-dibenzo [b,f]azepinyl, azepanyl, azetidinyl,aziridinyl, chromanyl, dithianyl, imidazolidinyl, imidazolinyl,indolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, succinimidyl,tetrahydrofuranyl, tetrahydropyranyl, thiochromanyl, thiomorpholinyl,trithianyl, xanthenyl and the like. It is understood that a heterocyclicgroup can be bonded only at any available ring carbon or ring nitrogenas allowed by the respective formulae unless otherwise specified.

The term “hydroxyl” is intended to mean the group —OH.

The term “nitro” is intended to mean the group —NO₂.

The term “sulfa)” is intended to mean the group —SO₃H.

The term “thiol” is intended to mean the group —SH.

Compounds of the Invention:

One aspect of the present invention pertains to certain compounds asshown in Formula (XIIIa):

and pharmaceutically acceptable salts, solvates and hydrates thereof;

wherein:

R¹, R², X and Q have the same definitions as described herein, supra andinfra.

One aspect of the present invention pertains to certain compounds asshown in Formula (Ia):

and pharmaceutically acceptable salts, solvates and hydrates thereof;

wherein:

R¹, R² and X have the same definitions as described herein, supra andinfra.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment.

Conversely, various features of the invention, which are, for brevity,described in the context of a single embodiment, may also be providedseparately or in any suitable subcombination. All combinations of theembodiments pertaining to the chemical groups represented by thevariables (e.g, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, X and Q)contained within the generic chemical formulae described herein, forexample, (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im), (II), (XIIa),(XIIIc), (XIIIe), (XIIIg), (XIIIi), (XIIIk), (XIIIm) are specificallyembraced by the present invention just as if each and every combinationwas individually explicitly recited, to the extent that suchcombinations embrace compounds that result in stable compounds (i.e.,compounds that can be isolated, characterized and tested for biologicalactivity). In addition, all subcombinations of the chemical groupslisted in the embodiments describing such variables, as well as allsubcombinations of uses and medical indications described herein, arealso specifically embraced by the present invention just as if each andevery subcombination of chemical groups and subcombination of uses andmedical indications was individually and explicitly recited herein. Inaddition, all subcombinations of the salts, solvates, hydrates andcrystalline forms specifically exemplified herein, as well as allsubcombinations of uses thereof and medical indications related theretodescribed herein, are also specifically embraced by the presentinvention just as if each and every subcombination of salts, solvates,hydrates and crystalline forms specifically exemplified herein andsubcombination of uses thereof and medical indications related theretowas individually and explicitly recited herein.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.Likewise. “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one group they can be identical or they canbe different.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers and the like. Tautomeric forms can be in equilibriumor sterically locked into one form by appropriate substitution. It isunderstood that the various tautomeric forms are within the scope of thecompounds of the present invention.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates and/or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include deuterium and tritium.

It is understood and appreciated that compounds of Formula (Ia) andformulae related thereto may have one or more chiral centers andtherefore can exist as enantiomers and/or diastereoisomers. Theinvention is understood to extend to and embrace all such enantiomers,diastereoisomers and mixtures thereof, including but not limited toracemates. It is understood that compounds of Formula (Ia) and formulaeused throughout this disclosure are intended to represent all individualenantiomers and mixtures thereof, unless stated or shown otherwise.

It is understood and appreciated that compounds of Formula (Ia) andformulae related thereto exist as meso isomers. Such meso isomers may bereferred to as cis and trans. The cis meso isomers of compounds ofFormula (Ia) are named herein using the prefix (1s,4s) and the transmeso isomers of compounds of Formula (Ia) are named herein using theprefix (1r,4r) as shown below:

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula (XIIIa) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen;

X is O or NR³;

R¹ is selected from H and C₁-C₆ alkyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H, 1-carboxyethylamino,1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino,1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino,4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino,carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino,1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,5-amino-1-carboaypentylamino, 1-carboxy-3-(methylthio)propylamino,1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,1-carboxy-2-(1H-indol-3-yl)ethylamino,1-carboxy-2-(4-hydroxyphenyl)ethylamino and1-carboxy-2-methylpropylamino.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula (Ia) and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, hydroxyl andhalogen;

X is O or NR³; and

R³ is selected from H and C₁-C₆ alkyl.

One aspect of the present invention encompasses certain cyclohexanederivatives selected from compounds of Formula (Ia) and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen;

X is O or NR³; and

R³ is selected from H and C₁-C₆ alkyl.

The Group R¹:

In some embodiments, R¹ is selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy.C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is selected from: C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is selected from: C₁-C₆ alkyl, aryl andheteroaryl; each optionally substituted with one or two substituentsselected from: methoxy, ethoxy, methyl, phenyl, trifluoromethyl,trifluoromethoxy, fluoro and chloro.

In some embodiments, R¹ is selected from: diphenylmethyl,2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl,4-methoxyphenyl, 4-tolyl, 5-(trifluromethyl)pyridin-2-yl,5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl,5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiazol-2-yl,5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl,pyridin-2-yl and pyridin-3-yl.

In some embodiments, R¹ is selected from: C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one, two or three substituents selected from: C₁-C₆acyl, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylcarboxamide, C₅-C₆ alkylsulfanyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonamide, C₁-C₆ alkylsulfonyl, amino, aryl, carbo-C₁-C₆-alkoxy,carboxamide, carboxy, cyano, C₂-C₈ dialkylamino, C₂-C₈dialkylcarboxamide, C₂-C₈ dialkyl sulfonamide, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, hydroxyl and nitro.

In some embodiments, R¹ is diphenylmethyl.

In some embodiments, R¹ is 2,3-difluorophenyl.

In some embodiments, R¹ is 2-fluoro-3-methoxyphenyl.

In some embodiments, R¹ is 2-fluorophenyl.

In some embodiments, R¹ is 2-fluoropyridin-4-yl.

In some embodiments, R¹ is 2-methoxyphenyl.

In some embodiments, R¹ is 3-(trifluoromethoxy)phenyl.

In some embodiments, R¹ is 3,4-difluorophenyl.

In some embodiments, R¹ is 3,5-difluorophenyl.

In some embodiments, R¹ is 3,5-dimethylphenyl.

In some embodiments, R¹ is 3-chloro-2-fluorphenyl.

In some embodiments, R¹ is 3-chloro-4-fluorphenyl.

In some embodiments, R¹ is 3-chloro-5-fluorphenyl.

In some embodiments, R¹ is 3-chlorophenyl.

In some embodiments, R¹ is 3-fluoro-4-methylphenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R¹ is 3-methoxyphenyl.

In some embodiments, R¹ is 3-tolyl.

In some embodiments, R¹ is 3-(trifluoromethyl)phenyl.

In some embodiments, R¹ is 4-(trifluoromethoxy)phenyl.

In some embodiments, R¹ is 4-chloro-3-fluorophenyl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 4-ethoxyphenyl.

In some embodiments, R¹ is 4-fluorophenyl.

In some embodiments, R¹ is 4-methoxy-2-methylphenyl.

In some embodiments, R¹ is 4-methoxyphenyl.

In some embodiments, R¹ is 4-tolyl.

In some embodiments, R¹ is 5-(trifluoromethyl)pyridin-2-yl.

In some embodiments, R¹ is 5-chloropyridin-2-yl.

In some embodiments, R¹ is 5-fluoropyridin-2-yl.

In some embodiments, R¹ is 5-fluoropyridin-3-yl.

In some embodiments, R¹ is 5-methoxypyridin-3-yl.

In some embodiments, R¹ is 5-methylpyridin-3-yl.

In some embodiments, R¹ is 5-methylthiazol-2-yl.

In some embodiments, R¹ is 5-methylthiophen-2-yl.

In some embodiments, R¹ is 6-fluoropyridin-3-yl.

In some embodiments, R¹ is phenyl.

In some embodiments, R¹ is pyrazin-2-yl.

In some embodiments, R¹ is pyridin-2-yl.

In some embodiments, R¹ is pyridin-3-yl.

The Group R²:

In some embodiments, R¹ is selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R² is selected from: H, C₁-C₆ alkyl and aryl;wherein said aryl is optionally substituted with one or two substituentsselected from: C₁-C₆ alkyl and halogen.

In some embodiments, R² is selected from: H, C₁-C₆ alkyl and aryl;wherein said aryl is optionally substituted with one or two substituentsselected from: methyl and fluoro.

In some embodiments, R² is selected from: H, methyl, n-propyl, phenyl,3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl.

In some embodiments, R² is selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen andhydroxy.

In some embodiments, R² is selected from: H, C₁-C₆ alkyl and aryl;wherein said aryl is optionally substituted with one or two substituentsselected from: C₁-C₆ alkyl, halogen and hydroxy.

In some embodiments, R² is selected from: H, C₁-C₆ alkyl and aryl;wherein said aryl is optionally substituted with one or two substituentsselected from: methyl, fluoro and hydroxy.

In some embodiments, R² is selected from: H, methyl, n-propyl, phenyl,3-tolyl, 4-tolyl, 3-fluorophenyl, 4-fluorophenyl and 4-hydroxyphenyl.

In some embodiments, R¹ is H.

In some embodiments, R¹ is methyl.

In some embodiments, R¹ is phenyl.

In some embodiments, R² is 3-tolyl.

In some embodiments, R² is 4-tolyl.

In some embodiments, R² is 3-fluorophenyl.

In some embodiments, R² is 4-fluorophenyl.

In some embodiments, R² is 4-hydroxyphenyl.

The Group R³:

In some embodiments, R³ is H.

In some embodiments, R³ is C₁-C₆ alkyl.

In some embodiments, R³ is methyl.

The Group X:

In some embodiments, X is O.

In some embodiments, X is NR³.

The Group O:

In some embodiments, Q is OH.

In some embodiments, Q is —NHCH₂CH₂SO₃H.

In some embodiments, Q is selected from: 1-carboxyethylamino,1-carboxy-4-guanidinobutyl amino, 3-amino-1-carboxy-3-oxopropyl amino,1,2-dicarboxyethylamino, 1-carboxy-2 mercaptoethylamino,4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino,carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino,1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,1-carboxy-2-phenylethylamino, 2-carboxypyrrdidin-1-yl,1-carboxy-2-hydroxy ethylamino, 1-carboxy-2-hydroxypropylamino,1-carboxy-2-(1H-indol-3-yl)ethylamino, 1-carboxy-2-(4hydroxyphenyl)ethylamino and 1-carboxy-2-methylpropylamino.

In some embodiments, Q is selected from: (S)-1-carboxyethylamino,(S)-1-carboxy-4-guanidinobutylamino,(S)-3-amino-1-carboxy-3-oxopropylamino, (S)-1,2-dicarboxyethylamino,(S)-1-carboxy-2-mercaptoethylamino,(S)-4-amino-1-carboxy-4-oxobutylamino,(S)-3-carboxy-1-carboxylatopropylamino, carboxymethylamino,(S)-1-carboxy-2-(1H-imidazol-4-yl)ethylamino,(1S,2S)-1-carboxy-2-methylbutylamino, (S-1-carboxy-3-methylbutylamino,(S)-5-amino-1-carboxypentylamino,(S)-1-carboxy-3-(methylthio)propylamino,(S)-1-carboxy-2-phenylethylamino, (S)-2-carboxypyrrolidin-1-yl,(S)-1-carboxy-2-hydroxyethylamino, (1S,2R)-1-caboxy-2-hydroxypropylamino.(S)-1-carboxy-2-(1H-indol-3-yl)ethylamino.(5)-1-carboxy-2-(4-hydroxyphenyl)ethylamino and(S)-1-carboxy-2-methylpropylamino.

In some embodiments, Q is 1-carboxyethylamino.

In some embodiments, Q is 1-carboxy-4-guanidinobutylamino.

In some embodiments, Q is 3-amino-1-carboxy-3-oxopropylamino.

In some embodiments, Q is 1,2-dicarboxyethylamino.

In some embodiments, Q is 1-carboxy-2-mercaptoethylamino.

In some embodiments, Q is 4-amino-1-carboxy-4-oxobutylamino.

In some embodiments, Q is 3-carboxy-1-carboxylatopropylamino.

In some embodiments, Q is carboxymethylamino.

In some embodiments, Q is 1-carboxy-2-(1H-imidazol-4-ylethylamino.

In some embodiments, Q is 1-carboxy-2-methylbutylamino.

In some embodiments, Q is 1-carboxy-3-methylbutylamino.

In some embodiments, Q is 5-amino-1-carboxypentylamino.

In some embodiments, Q is 1-carboxy-3-(methylthio)propylamino.

In some embodiments, Q is 1-carboxy-2-phenylethylamino.

In some embodiments, Q is 2-carboxypyrrolidin-1-yl.

In some embodiments, Q is 1-carboxy-2-hydroxyethylamino.

In some embodiments, Q is 1-carboxy-2-hydroxypropylamino.

In some embodiments, Q is 1-carboxy-2-(1H-indol-3-yl)ethylamino.

In some embodiments, Q is 1-carboxy-2-(4-hydroxy phenyl)ethylamino.

In some embodiments, Q is 1-carboxy-2-methylpropylamino.

In some embodiments, Q is (S)-1-carboxyethylamino.

In some embodiments, Q is (S)-1-carboxy-4-guanidinobutylamino.

In some embodiments, Q is (S)-3-amino-1-carboxy-3-oxopropylamino.

In some embodiments, Q is (S)-1,2-dicarboxyethylamino.

In some embodiments, Q is (S)-1-carboxy-2-mercaptoethylamino.

In some embodiments, Q is (S)-4-amino-1-carboxy-4-oxobutylamino.

In some embodiments, Q is (S)-3-carboxy-1-carboxylatopropylamino.

In some embodiments, Q is carboxymethylamino.

In some embodiments, Q is (S)-1-carboxy-2-(1H-imidazol-1-yl)ethylamino.

In some embodiments, Q is (1S,2S)-1-carboxy-2-methylbutylamino.

In some embodiments, Q is (S)-1-carboxy-3-methylbutylamino.

In some embodiments, Q is (S)-5-amino-1-carboxypentylamino.

In some embodiments, Q is (S)-1-carboxy-3-(methylthio)propylamino.

In some embodiments, Q is (5)-1-carboxy-2-phenylethylamino.

In some embodiments, Q is (S)-2-carboxypyrrolidin-1-yl.

In some embodiments, Q is (S)-1-carboxy-2-hydroxyethylamino.

In some embodiments, Q is (1S,2R)-1-carboxy-2-hydroxypropylamino.

In some embodiments, Q is (S)-1-carboxy-2-(1H-indol-3-yl)ethylamino.

In some embodiments, Q is (S)-1-carboxy-2-(4-hydroxyphenyl)ethylamino.

In some embodiments, Q is (S)-1-carboxy-2-methylpropylamino.

Certain Combinations of the Present Invention:

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (XIIIc) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen;

X is O or NR³;

R³ is selected from H and C₁-C₆ alkyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H, 1-carboxyethylamino,1-carboxy-1-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino,1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino,4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino,carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino,1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,1-carboxy-2-(1H-indol-3-yl)ethylamino,1-carboxy-2-(4-hydroxyphenyl)ethylamino and1-carboxy-2-methylpropylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (XIIIc) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-1-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl;

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl;

X is O or NR³;

R¹ is selected from H and methyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H and carboxymethylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (XIIIe) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen:

X is O or NR³;

R³ is selected from H and C₁-C₆ alkyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H, 1-carboxyethylamino,1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino,1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino,4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino,carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino,1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,1-carboxy-2-phenylethylamino, 2-carboxypyrrdidin-1-yl,1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,1-carboxy-2-(1H-indol-3-yl)ethylamino,1-carboxy-2-(4-hydroxyphenyl)ethylamino and1-carboxy-2-methylpropylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (XIIIe) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl;

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl;

X is O or NR³;

R³ is selected from H and methyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H and carboxymethylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (XIIIg) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R³ is selected from H and C₁-C₆ alkyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H, 1-carboxyethylamino,1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino,1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino,4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino,carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino,1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,5-amino-1-carboxy pentylamino, 1-carboxy-3-(methylthio)propylamino,1-carboxy-2-phenylethylamino, 2-carboxypyrrdidin-1-yl,1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino1-carboxy-2-(1H-indol-3-yl)ethylamino,1-carboxy-2-(4-hydroxyphenyl)ethylamino and1-carboxy-2-methylpropylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (Xing) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl;

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl;

R³ is selected from H and methyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H and carboxymethylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (XIIIi) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen;

R³ is selected from H and C₁-C₆ alkyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H, 1-carboxyethylamino,1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino,1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino,4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino,carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino,l-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,5-amino-1-carbaxypentylamino, 1-carboxy-3-(methylthio)propylamino,1-carboxy-2-phenylethylamino, 2-carboxypyrrolidin-1-yl,1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,1-carboxy-2-(1H-indol-3-yl)ethylamino,1-carboxy-2-(4-hydroxyphenyl)ethylamino and1-carboxy-2-methylpropylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (XIIIi) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl;

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl:

R³ is selected from H and methyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H and carboxymethylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (XIIIk) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and Qis selected from: OH, —NHCH₂CH₂SO₃H, 1-carboxyethylamino,1-carboxy-4-guanidinobutylamino, 3-amino-1-carboxy-3-oxopropylamino,1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino,4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-l-carboxylatopropylamino,carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino,1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,1-carboxy-2-phenylethylamino, 2-carboxypyrrdidin-1-yl,1-carboxy-2-hydroxyethylamino, 1-carboxy-2-hydroxypropylamino,1-carboxy-2-(1H-indol-3-yl)ethylamino,1-carboxy-2-(4-hydroxyphenyl)ethylamino and1-carboxy-2-methylpropylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (XIIIk) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl;

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H and carboxymethylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (XIIIm) andpharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

Q is selected from: OH, —NHCH₂CH₂SO₃H, 1-carboxyethylamino,1-carboxy-4-guanidinobutylamino, 3-amino-1-car boxy-3-oxopropylamino,1,2-dicarboxyethylamino, 1-carboxy-2-mercaptoethylamino,4-amino-1-carboxy-4-oxobutylamino, 3-carboxy-1-carboxylatopropylamino,carboxymethylamino, 1-carboxy-2-(1H-imidazol-4-yl)ethylamino,1-carboxy-2-methylbutylamino, 1-carboxy-3-methylbutylamino,5-amino-1-carboxypentylamino, 1-carboxy-3-(methylthio)propylamino,1-carboxy-2-phenylethylamino, 2-carboxypyrrdidin-1-yl,1-carboxy-2-hydroxy ethylamino, 1-carboxy-2-hydroxypropylamino,1-carboxy-2-(1H-indol-3-yl)ethylamino,1-carboxy-2-(4-hydroxyphenyl)ethylamino and1-carboxy-2-methylpropylamino.

The compound according to claim 1, selected from compounds of Formula(XIIIm) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxy phenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl;

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl; and

Q is selected from: OH, —NHCH₂CH₂SO₃H and carboxymethylamino.

One aspect of the present invention encompasses certain amidederivatives selected from compounds of Formula (Ia) and pharmaceuticallyacceptable salts, solvates and hydrates thereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one, two or three substituents selected from: C₁-C₆aryl, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylcarboxamide, C₁-C₆ alkylsulfanyl, C₁-C₆ allylsulfamyl, C₁-C₆alkylsulfonamide, C₁-C₆ alkylsulfonyl, amino, aryl, carbo-C₁-C₆-alkoxy,carboxamide, carboxy, cyano, C₂-C₈ dialkylamino, C₂-C₈dialkylcarboxamide, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, hydroxyl and nitro:

X is O or NR³; and

R³ is selected from H and C₁-C₆ alkyl.

In some embodiments, R¹ and R² are each independently selected from: H,C₁-C₆ alkyl, aryl and heteroaryl; wherein C₁-C₆ alkyl, aryl andheteroaryl are each optionally substituted with one, two or threesubstituents selected from: C₁-C₆ acyl, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆alkylamino, C₁-C₆ alkylcarboxamide, C₁-C₆ alkylsulfanyl, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonamide, C₁-C₆ alkylsulfonyl, amino, aryl,carbo-C₁-C₆-alkoxy, carboxamide, carboxy, cyano, C₂-C₈ dialkylamino,C₂-C₈ dialkylcarboxamide, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkoxy,C₁-C₆haloalkyl, halogen, hydroxyl and nitro.

In some embodiments, R¹ is selected from: C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one, two or three substituents selected from: C₁-C₆acyl, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylcarboxamide, C₁-C₆ alkylsulfanyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonamide, C₁-C₆ alkylsulfonyl, amino, aryl, carbo-C₁-C₆-alkoxy,carboxamide, carboxy, cyano, C₂-C₈ dialkylamino, C₂-C₈dialkylcarboxamide, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, hydroxyl and nitro; and R² is selected from: H,C₁-C₆ alkyl and aryl; wherein said aryl is optionally substituted withone or two substituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R¹ is selected from: C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one, two or three substituents selected from: C₁-C₆acyl, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylcarboxamide, C₁-C₆ alkylsulfanyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonamide, C₁-C₆ alkylsulfonyl, amino, aryl, carbo-C₁-C₆-alkoxy,carboxamide, carboxy, cyano, C₂-C₈ dialkylamino, C₂-C₈dialkylcarboxamide, C₂-C₈ dialkylsulfonamide, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, halogen, hydroxyl and nitro; and R¹ is selected from: H,methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-flurophenyl and4-fluorophenyl.

In some embodiments, R¹ and R² are each independently selected from: H,C₁-C₆ alkyl, aryl and heteroaryl; wherein C₁-C₆ alkyl, aryl andheteroaryl are each optionally substituted with one or two substituentsselected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl and halogen.

In some embodiments, R¹ and R² are each independently selected from: H,C₁-C₆ alkyl, aryl and heteroaryl; wherein C₁-C₆ alkyl, aryl andheteroaryl are each optionally substituted with one or two substituentsselected from: methoxy, ethoxy, methyl, phenyl, trifluoromethyl,trifluoromethoxy, fluoro and chloro.

In some embodiments, R¹ and R² are each independently selected from: H,diphenylmethyl, 2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl,2-fluorophenyl, 2-fluoropyridin-4-yl, 2-methoxyphenyl,3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,3,5-dimethylphenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl, 4ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl, 4-methoxyphenyl,4-tolyl, 5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, methyl, phenyl, n-propyl, pyrazin-2-yl,pyridin-2-yl and pyridin-3-yl.

In some embodiments, R¹ is selected from: C₁-C₆ alkyl, aryl andheteroaryl; each optionally substituted with one or two substituentsselected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl and halogen; and R² is selected from: H, C₁-C₆ alkyl and aryl;wherein said aryl is optionally substituted with one or two substituentsselected from: C₁-C₆ alkyl and halogen.

In some embodiments, R¹ is selected from: C₁-C₆ alkyl, aryl andheteroaryl; each optionally substituted with one or two substituentsselected from: methoxy, ethoxy, methyl, phenyl, trifluoromethyl,trifluoromethoxy, fluoro and chloro; and R² is selected from: H, C₁-C₆alkyl and aryl; wherein said aryl is optionally substituted with one ortwo substituents selected from: methyl and fluoro.

In some embodiments, R¹ is selected from: diphenylmethyl,2,3-difluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluorophenyl,2-fluoropyridin-4-yl, 2-methoxyphenyl, 3-(trifluoromethoxy)phenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl,3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,3-chloro-5-fluorophenyl, 3-chlorophenyl, 3-fluoro-4-methylphenyl,3-fluorophenyl, 3-methoxyphenyl, 3-tolyl, 3-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl, 4-chloro-3-fluorophenyl, 4-chlorophenyl,4-ethoxyphenyl, 4-fluorophenyl, 4-methoxy-2-methylphenyl,4-methoxyphenyl, 4-tolyl, 5-(trifluoromethyl)pyridin-2-yl,5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 5 fluoropyridin-3-yl,5-methoxypyridin-3-yl, 5-methylpyridin-3-yl, 5-methylthiazol-2-yl,5-methylthiophen-2-yl, 6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl,pyridin-2-yl and pyridin-3-yl; and R² is selected from: H, methyl,n-propyl, phenyl, 3-tolyl, 4-tolyl, 3-fluorophenyl and 4-fluorophenyl.

The embodiments of the present invention pertain to compounds of Formula(Ic) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy. C₁-C₆ haloalkyl and halogen;

X is O or NR³; and

R³ is selected from H and C₁-C₆ alkyl.

The embodiments of the present invention pertain to compounds of Formula(Ic) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl;

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl;

X is O or NR³; and

R³ is selected from H and methyl.

The embodiments of the present invention pertain to compounds of Formula(Ie) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen;

X is O or NR³; and

R³ is selected from H and C₁-C₆ alkyl.

The embodiments of the present invention pertain to compounds of Formula(Ie) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-1-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-meth oxy phenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl:

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl:

X is O or NR³; and

R¹ is selected from H and methyl.

The embodiments of the present invention pertain to compounds of Formula(Ig) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R³ is selected from H and C₁-C₆ alkyl.

The embodiments of the present invention pertain to compounds of Formula(Ig) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4 difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chiorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5 fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl;

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl; and

R³ is selected from H and methyl.

The embodiments of the present invention pertain to compounds of Formula(Ii) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R³ is selected from H and C₁-C₆ alkyl.

The embodiments of the present invention pertain to compounds of Formula(ii) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5 methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl;

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl; and

R³ is selected from H and methyl.

The embodiments of the present invention pertain to compounds of Formula(Ik) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen.

The embodiments of the present invention pertain to compounds of Formula(Ik) and

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-4-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-211, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl; and

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl.

The embodiments of the present invention pertain to compounds of Formula(Im) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen.

The embodiments of the present invention pertain to compounds of Formula(Im) and pharmaceutically acceptable salts, solvates and hydratesthereof:

wherein:

R¹ is selected from: diphenylmethyl, 2,3-difluorophenyl,2-fluoro-3-methoxyphenyl, 2-fluorophenyl, 2-fluoropyridin-1-yl,2-methoxyphenyl, 3-(trifluoromethoxy)phenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3,5-dimethylphenyl, 3-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chlorophenyl,3-fluoro-4-methylphenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-tolyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,4-chloro-3-fluorophenyl, 4-chlorophenyl, 4-ethoxyphenyl, 4-fluorophenyl,4-methoxy-2-methylphenyl, 4-methoxyphenyl, 4-tolyl,5-(trifluoromethyl)pyridin-2-yl, 5-chloropyridin-2-yl,5-fluoropyridin-2-yl, 5-fluoropyridin-3-yl, 5-methoxypyridin-3-yl,5-methylpyridin-3-yl, 5-methylthiazol-2-yl, 5-methylthiophen-2-yl,6-fluoropyridin-3-yl, phenyl, pyrazin-2-yl, pyridin-2-yl andpyridin-3-yl; and

R² is selected from: H, methyl, n-propyl, phenyl, 3-tolyl, 4-tolyl,3-fluorophenyl and 4-fluorophenyl.

The embodiments of the present invention include every combination ofone or more compounds selected from the following group;

-   2-((-4-(3-benzhydrylureido)methyl)cyclohexyl)methoxy)acetic acid;-   2-((-4-(3,3-diphenylureido)methyl)cyclohexyl)methoxy)acetic acid;-   2-((-4-((3-(3-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((1-methyl-3,3-diphenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;-   2-((-4-((3-(3-chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(4-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(2-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(4-chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-phenyl-3-m-tolylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-phenyl-3-p-tolylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3,3-di p-tolylureido)methyl)cyclohexyl)methoxy)acetic acid;-   2-((-4-((3,3-di m-tolylureido)methyl)cyclohexyl)methoxy)acetic acid;-   2-((-4-((3-(3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(4-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(4-methoxy-2-methylphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-phenyl-3-(3-(trifluoromethyl)phenyl)ureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)ecetic    acid;-   2-((-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-chlorophenyl)(phenyl)carbamoylaxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid;-   2-((-4-(((2-methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((phenyl(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-fluorophenylxphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-chloro-3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-chloro-4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluoro-4-methylphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3,5-difluorophenylXphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3,4-difluorophenylXphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(2,3-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(3,5-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(3-chloro-2-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-chloro-5-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(3-chloro-5-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-benzhydryl-3-methylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((phenyl(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((5-methylthiophen-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((2,3-difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(4-chloro-3-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-(2-fluoro-3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-3,4-difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluorophenyl)(4-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluorophenylXm-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-chloro-3-fluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-chloro-4-fluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluoro-4-methylphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((phenyl(pyridin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3,5-difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3,4-difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((bis(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluorophenyl)(3-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3,5-dimethylphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluorophenyl)(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluorophenyl)(6-fluoropyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluorophenyl)(5-methylthiophen-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-ethoxyphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluorophenyl)(3-(trifluoromethoxy)phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid,-   2-((-4-(((3-fluorophenyl)(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-fluorophenyl)(5-methylthiophen-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((3-chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid,-   2-((-4-(((4-ethoxyphenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-fluorophenyl)(4-(trifluoromethoxy)phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((bis(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((6-fluoropyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((phenyl(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((benrhydryl(methyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((3-benzhydryl-1,3-dimethylureido)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((4-ethoxyphenylxphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((2-fluoropyridin-4-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((5-methoxypyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((5-fluoropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-((phenyl(5-(trifluoromethyl)pyridin-2-yl)carbamoyloxy)methyl)cyclohexyl    methoxy)acetic acid;-   2-((-4-(((5-methylpyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((5-chloropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid;-   2-((-4-(((5-fluoropyridin-3-yl)phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid-   2-((-4-((benzhydryl(propyl)calhamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid; and-   2-((-4-(((5-methylthiazol-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic    acid.

The embodiments of the present invention include every combination ofone or more compounds selected from the following group shown in TABLEA.

TABLE A Cmpd No. Chemical Structure Chemical Name 1

2-(((1r,4r)-4-((3- benzhydrylureido)methyl)cyclo- hexyl)methoxy)aceticacid 2

2-(((1r,4r)-4-((3,3- diphenylureido)methyl)cyclo- hexyl)methoxy)aceticacid 3

2-(((1r,4r)-4-((3-(3- fluorophenyl)-3- phenylureido)methyl)cyclo-hexyl)methoxy)acetic acid 4

2-(((1r,4r)-4-((1-methyl-3,3- diphenylureido)methyl)cyclo-hexyl)methoxy)acetic acid 5

2-(((1r,4r)-4-((diphenyl- carbamoyloxy)methyl)cyclo-hexyl)methoxy)acetic acid 6

2-(((1r,4r)-4-((3-(3- chlorophenyl)-3- phenylureido)methyl)cyclo-hexyl)methoxy)acetic acid 7

2-(((1s,4s)-4-((diphenyl- carbamoyloxy)methyl)cyclo-hexyl)methoxy)acetic acid 8

2-(((1r,4r)-4-((3-(4- fluorophenyl)-3- phenylureido)methyl)cyclo-hexyl)methoxy)acetic acid 9

2-(((1s,4s)-4-((3,3- diphenylureido)methyl)cyclo- hexyl)methoxy)aceticacid 10

2-(((1r,4r)-4-((3-(2- fluorophenyl)-3- phenylureido)methyl)cyclo-hexyl)methoxy)acetic acid 11

2-(((1r,4r)-4-((3-(4- chlorophenyl)-3- phenylureido)methyl)cyclo-hexyl)methoxy)acetic acid 12

2-(((1r,4r)-4-((3-phenyl-3-m- tolylureido)methyl)cyclo-hexyl)methoxy)acetic acid 13

2-(((1r,4r)-4-((3-phenyl-3-p- tolylureido)methyl)cyclo-hexyl)methoxy)acetic acid 14

2-(((1r,4r)-4-(((3- methoxyphenyl)(phenyl)carba- moyloxy)methyl)cyclo-hexyl)methoxy)acetic acid 15

2-(((1r,4r)-4-((3,3-di p- tolylureido)methyl)cyclo- hexyl)methoxy)aceticacid 16

2-(((1r,4r)-4-((3,3-di m- tolylureido)methyl)cyclo- hexyl)methoxy)aceticacid 17

2-(((1r,4r)-4-((3-(3- methoxyphenyl)-3- phenylureido)methyl)cyclo-hexyl)methoxy)acetic acid 18

2-(((1r,4r)-4-((3-(4- methoxyphenyl)-3- phenylureido)methyl)cyclo-hexyl)methoxy)acetic acid 19

2-(((1r,4r)-4-((3-(4-methoxy-2- methylphenyl)-3-phenylureido)methyl)cyclo- hexyl)methoxy)acetic acid 20

2-(((1r,4r)-4-((3-phenyl-3-(3- (trifluoromethyl)phenyl)ure-ido)methyl)cyclo- hexyl)methoxy)acetic acid 21

2-(((1r,4r)-4-(((4-methoxy- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 22

2-(((1r,4r)-4-(((4-chloro- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 23

2-(((1r,4r)-4-(((3-fluoro- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 24

2-(((1s,4s)-4-(((4-methoxy- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 25

2-(((1s,4s)-4-(((4-chloro phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 26

2-(((1s,4s)-4-(((3-fluoro- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 27

2-(((1r,4r)-4-((phenyl(m- tolyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 28

2-(((1r,4r)-4-(((3-chloro- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 29

2-(((1r,4r)-4-((phenyl- carbamoyloxy)methyl)cyclo- hexyl)methoxy)aceticacid 30

2-(((1s,4s)-4-(((3-chloro- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 31

2-(((1s,4s)-4-((phenyl(m- tolyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 32

2-(((1s,4s)-4-(((2-methoxy- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 33

2-(((1s,4s)-4-(((3-methoxy- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 34

2-(((1s,4s)-4-((phenyl(p- tolyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 35

2-(((1s,4s)-4-(((4-fluoro- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 36

2-(((1r,4r)-4-(((4-chloro-3-fluoro- phenyl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 37

2-(((1r,4r)-4-(((3-chloro-4-fluoro- phenyl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 38

2-(((1r,4r)-4-(((3- fluoro-4-methyl- phenyl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 39

2-(((1r,4r)-4-(((3,5-difluoro- phenyl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 40

2-(((1r,4r)-4-(((3,4-difluoro- phenyl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 41

2-(((1r,4r)-4-(((4-fluoro- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 42

2-(((1r,4r)-4-((phenyl(p- tolyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 43

2-(((1r,4r)-4-((3-(2,3- difluorophenyl)-3-phenyl- ureido)methyl)cyclo-hexyl)methoxy)acetic acid 44

2-(((1r,4r)-4-((3-(3,5- difluorophenyl)-3-phenyl- ureido)methyl)cyclo-hexyl)methoxy)acetic acid 45

2-(((1r,4r)-4-((3-(3-chloro-2- fluorophenyl)-3-phenyl-ureido)methyl)cyclo- hexyl)methoxy)acetic acid 46

2-(((1r,4r)-4- (((3-chloro-5-fluoro- phenyl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 47

2-(((1r,4r)-4-((3-(3-chloro-5- fluorophenyl)-3-phenyl-ureido)methyl)cyclo- hexyl)methoxy)acetic acid 48

2-(((1r,4r)-4-((3-benzhydryl-3- methylureido)methyl)cyclo-hexyl)methoxy)acetic acid 49

2-(((1r,4r)-4-((phenyl(pyridin-3- yl)carbamoyloxy)methyl)cyclo-hexyl)methoxy)acetic acid 50

2-(((1r,4r)-4-(((5-methylthiophen- 2-yl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 51

2-(((1r,4r)-4-(((2,3-difluoro- phenyl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 52

2-(((1r,4r)-4-((3-(4-chloro-3- fluorophenyl)-3-phenyl-ureido)methyl)cyclo- hexyl)methoxy)acetic acid 53

2-(((1r,4r)-4-((3-(2-fluoro-3- methoxyphenyl)-3-phenyl-ureido)methyl)cyclo- hexyl)methoxy)acetic acid 54

2-(((1r,4r)-4-((3-(3,4- difluorophenyl)-3-phenyl- ureido)methyl)cyclo-hexyl)methoxy)acetic acid 55

2-(((1r,4r)-4-(((3- fluorophenyl)(4-methoxy- phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 56

2-(((1r,4r)-4-(((4- chlorophenyl)(3- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 57

2-(((1r,4r)-4-(((3- fluorophenyl)(4- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 58

2-(((1r,4r)-4-(((3- chlorophenyl)(3- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 59

2-(((1r,4r)-4-(((3- fluorophenyl)(m- tolyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 60

2-(((1r,4r)-4-(((4-chloro-3- fluorophenyl)(3- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 61

2-(((1r,4r)-4-(((3-chloro-4- fluorophenyl)(3- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 62

2-(((1r,4r)-4-(((3-fluoro-4- methylphenyl)(3- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 63

2-(((1r,4r)-4-((phenyl(pyridin-2- yl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 64

2-(((1r,4r)-4-(((3,5- difluorophenyl)(3- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 65

2-(((1r,4r)-4-(((3,4- difluorophenyl)(3- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 66

2-(((1r,4r)-4-((bis(3- fluorophenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 67

2-(((1r,4r)-4-(((3- fluorophenyl)(3- methoxyphenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 68

2-(((1r,4r)-4-(((3,5- dimethylphenyl)(3- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 69

2-(((1r,4r)-4-(((3- fluorophenyl)(p- tolyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 70

2-(((1r,4r)-4-(((3- fluorophenyl)(6-fluoro- pyridin-3-yl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 71

2-(((1r,4r)-4-(((3-fluoro- phenyl)(5-methylthiophen- 2-yl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 72

2-(((1r,4r)-4-(((4- ethoxyphenyl)(3- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 73

2-(((1r,4r)-4-(((3- fluorophenyl)(3-(trifluoro-methoxy)phenyl)carbamoyl- oxy)methyl)cyclo- hexyl)methoxy)acetic acid 74

2-(((1r,4r)-4-(((3- fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclo- hexyl)methoxy)acetic acid 75

2-(((1r,4r)-4-(((3- fluorophenyl)(pyrazin-2- yl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 76

2-(((1r,4r)-4-(((4- chlorophenyl)(4- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 77

2-(((1r,4r)-4-(((4-fluoro- phenyl)(5-methylthiophen- 2-yl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 78

2-(((1r,4r)-4-(((3- chlorophenyl)(4- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 79

2-(((1r,4r)-4-(((4- fluorophenyl)(pyridin-3- yl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 80

2-(((1r,4r)-4-(((4- ethoxyphenyl)(4- fluorophenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 81

2-(((1r,4r)-4-(((4- fluorophenyl)(4-(trifluoro-methoxy)phenyl)carbamoyl- oxy)methyl)cyclo- hexyl)methoxy)acetic acid 82

2-(((1r,4r)-4-(((4- fluorophenyl)(m- tolyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 83

2-(((1r,4r)-4-((bis(4- fluorophenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 84

2-(((1r,4r)-4-(((6- fluoropyridin-3- yl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 85

2-(((1r,4r)-4- ((phenyl(pyrazin-2- yl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 86

2-(((1r,4r)-4-((benz- hydryl(methyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 87

2-(((1r,4r)-4-((3- benzhydryl-1,3-dimethyl- ureido)methyl)cyclo-hexyl)methoxy)acetic acid 88

2-(((1r,4r)-4-(((4-ethoxy- phenyl)(phenyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 89

2-(((1r,4r)-4-(((2- fluoropyridin-4- yl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 90

2-(((1r,4r)-4-(((5- methoxypyridin-3- yl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 91

2-(((1r,4r)-4-(((5- fluoropyridin-2- yl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 92

2-(((1r,4r)-4-((phenyl(5- (trifluoromethyl)pyridin-2- yl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 93

2-(((1r,4r)-4-(((5- methylpyridin- 3-yl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 94

2-(((1r,4r)-4-(((5- chloropyridin-2- yl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 95

2-(((1r,4r)-4-(((5- fluoropyridin-3- yl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 96

2-(((1r,4r)-4-((benz- hydryl(propyl)carbamoyl- oxy)methyl)cyclo-hexyl)methoxy)acetic acid 97

2-(((1r,4r)-4-(((5- methylthiazol- 2-yl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 98

2-(((1r,4r)-4-(((4- chlorophenyl)(4- hydroxyphenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acetic acid 99

2-(2-(((1r,4r)-4-(((4-chloro- phenyl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acet- amido)ethanesulfonic acid 100

2-(2-(((1r,4r)-4-(((4-chloro- phenyl)(phenyl)carbamoyl-oxy)methyl)cyclo- hexyl)methoxy)acet- amido)acetic acid

Additionally, individual compounds and chemical genera of the presentinvention, for example those compounds found in TABLE A includingdiastereoisomers and enantiomers thereof, encompass all pharmaceuticallyacceptable salts, solvates and particularly hydrates, thereof. Further,mesoisomers of individual compounds and chemical genera of the presentinvention, for example those compounds found in TABLE A, encompass allpharmaceutically acceptable salts, solvates and particularly hydrates,thereof. The compounds of the Formula (Ia) of the present invention maybe prepared according to relevant published literature procedures thatare used by one skilled in the art. Exemplary reagents and proceduresfor these reactions appear hereinafter in the working Examples.

The embodiments of the present invention include every combination ofone or more salts selected from the following group and pharmaceuticallyacceptable solvates and hydrates thereof:

-   sodium    2-(((1r,4r)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate;-   sodium    2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate;-   sodium    2-(((1r,4r)-4-(((4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methcay)acetate;-   sodium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methooy)acetate;-   magnesium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate;-   potassium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate;    and-   calcium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate.

It is understood that the present invention embraces eachdiastereoisomer, each enantiomer and mixtures thereof of each compoundand generic formulae disclosed herein just as if they were eachindividually disclosed with the specific stereochemical designation foreach chiral carbon. Separation of the individual isomers (such as, bychiral HPLC, recrystallization of diastereoisomeric mixtures and thelike) or selective synthesis (such as, by enantiomeric selectivesyntheses and the like) of the individual isomers is accomplished byapplication of various methods which are well known to practitioners inthe art.

Indications and Methods of Prophylaxis and/or Treatment

In addition to the foregoing beneficial uses for the modulators of PGI2receptor activity disclosed herein, the compounds disclosed herein areuseful in the treatment of several additional diseases and disorders,and in the amelioration of symptoms thereof. Without limitation, theseinclude the following:

1. Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) has a multi factorialpathobiology. Vasoconstriction, remodeling of the pulmonary vessel wall,and thrombosis contribute to increased pulmonary vascular resistance inPAH (Humbert et al., J. Am. Coll. Cardiol., 2004, 43:13S-24S.)

The compounds of the present invention disclosed herein are useful inthe treatment of pulmonary arterial hypertension (PAH) and symptomsthereof. PAH shall be understood to encompass the following forts ofpulmonary arterial hypertension described in the 2003 World HealthOrganization (WHO) clinical classification of pulmonary arterialhypertension; idiopathic PAH (IPAH); familial PAH (FPAH); PAH associatedwith other conditions (APAH), such as PAH associated with collagenvascular disease, PAH associated with congenital systemic-to-pulmonaryshunts, PAH associated with portal hypertension. PAH associated with HIVinfection, PAH associated with drugs or toxins, or PAH associated withOther, and PAH associated with significant venous or capillaryinvolvement.

Idiopathic PAH refers to PAH of undetermined cause.

Familial PAH refers to PAH for which hereditary transmission issuspected or documented.

PAH associated with collagen vascular disease shall be understood toencompass PAH associated with scleroderma, PAH associated with CREST(calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction,sclerodactyly, and telangiectasias) syndrome, PAH associated withsystemic lupus erythematosus (SLE), PAH associated with rheumatoidarthritis, PAH associated with Takayasu's arteritis, PAH associated withpolymyositis, and PAH associated with dermatomyositis.

PAH associated with congenital systemic-to-pulmonary shunts shall beunderstood to encompass PAH associated with atrial septic defect (ASD),PAH associated with ventricular septic defect (VSD) and PAH associatedwith patent duals arteriosus.

PAH associated with drugs or toxins shall be understood to encompass PAHassociated with ingestion of aminorex, PAH associated with ingestion ofa fenfluramine compound (e.g., PAH associated with ingestion offenfluramine or PAH associated with ingestion of dexfenfluramine), PAHassociated with ingestion of certain toxic oils (e.g., PAH associatedwith ingestion of rapeseed oil), PAH associated with ingestion ofpyrrolizidine alkaloids (e.g., PAH associated with ingestion of bushtea) and PAH associated with ingestion of monocrotaline.

PAH associated with Other shall be understood to encompass PAHassociated with a thyroid disorder, PAH associated with glycogen storagedisease, PAH associated with Gaucher disease, PAH associated withhereditary hemorrhagic telangiectasia, PAH associated with ahemoglobinopathy, PAH associated with a myeloproliferitive disorder, andPAH associated with splenectomy.

PAH associated with significant venous or capillary involvement shall beunderstood to encompass PAH associated with pulmonary veno-occlusivedisease (PVOD) and PAH associated with pulmonary capillaryhemangiomatosis (PCH).

(See, e.g., Simonneau et al, J. Am. Coll. Cardid., 2004, 43:5S—12S;McGoon et al., Chest, 2004, 126:14S—34S; Rabinovitch, Anna Rev. Pathol.Mech. Dis., 2007, 2:369-399; McLaughlin et al., Circulation, 2006,114:1417-1431; Strauss et al., Clin. Chest Med., 2007, 28:127-142;Taichman et al., Clin. Chest. Med., 2007, 28:1-22.)

Evidence for the association of PAH with scleroderma and the beneficialeffect of an agonist of the PGI2 receptor on PAH is given by Badesch etal. (Badesch et al, Ann. Intern. Med., 2000, 132:425-434). Evidence forthe association of PAH with the collagen vascular diseases mixedconnective tissue disease (MCTD), systemic lupus erythematosus (SLE),Sjogren's syndrome and CREST syndrome and the beneficial effect of anagonist of the PCI2 receptor on PAH is given by Humbert et al. (Eur.Respir. J., 1999, 13:1351-1356). Evidence for the association of PAHwith CREST syndrome and the beneficial effect of an agonist of the PGI2receptor on PAH is given by Miwa et al (Int. Heart J., 2007,48:417-422). Evidence for the association of PAH with SLE and thebeneficial effect of an agonist of the PGI2 receptor on PAH is given byRobbins et al. (Chest, 2000, 117:14-18). Evidence for the association ofPAH with HIV infection and the beneficial of an agonist of the PGI2receptor on PAH is given by Aguilar et al. (Am J. Respir. Crit. CareMed., 2000, 162:1846-1850). Evidence for the association of PAH withcongenital heart defects (including ASD, VSD and patent ductusarteriosus) and the beneficial effect of an agonist of the PGI2 receptoron PAH is given by Rosenzweig et al (Circulation, 1999, 99:1858-1865).Evidence for the association of PAH with fenfluramine and withdexfenfluramine, anorexigens, is given by Ardier et al. (Am. J. Respir.Crit. Care Med., 1998, 158:1061-1067). Evidence for the association ofPAH with hereditary hemorrhagic telangiectasia is given by McGoon et al.(Chest, 2004, 126:14-34). Evidence for the association of PAH withsplenectomy is given by Hoeper et al. (Ann. Intern. Med., 1999,130:506-509). Evidence for the association of PAH with portalhypertension and the beneficial effect of an agonist of the PGI2receptor on PAH is given by Hoeper et al. (Eur. Respir. J., 2005,25:502-508).

Symptoms of PAH include dyspnea, angina, syncope and edema (McLaughlinel al. Circulation, 2006, 114:1417-1431). The compounds of the presentinvention disclosed herein are useful in the treatment of symptoms ofPAH

2. Antiplatelet Therapies (Conditions Related to Platelet Aggregation)

Antiplatelet agents (antiplatelets) are prescribed for a variety ofconditions. For example, in coronary artery disease they are used tohelp prevent myocardial infarction or stroke in patients who e at riskof developing obstructive blood clots (e g, coronary thrombosis).

In a myocardial infarction (“MI” or “heart attack”), the heart muscledoes not receive enough oxygen-rich blood as a result of a blockage inthe coronary blood vessels. If taken while an attack is in progress orimmediately afterward (preferably within 30 min), antiplateletS canreduce the damage to the heart.

A transient ischemic attack (“TIA” or “mini-stroke”) is a briefinterruption of oxygen flow to the brain due to decreased blood flowthrough arteries, usually due to an obstructing blood clot. Antiplateletdrugs have been found to be effective in preventing TIAs.

Angina is a temporary and often recurring chest pain, pressure ordiscomfort caused by inadequate oxygen-rich blood flow (ischemia) tosome parts of the heart. In patients with angina, antiplatelet therapycan reduce the effects of angina and the risk of myocardial infarction.

Stroke is an event in which the brain does not receive enoughoxygen-rich blood, usually due to blockage of a cerebral blood vessel bya blood clot. In high-risk patients, taking antiplatelets regularly hasbeen found to prevent the formation of blood clots that cause first orsecond strokes.

Angioplasty is a catheter based technique used to open arteriesobstructed by a blood clot Whether or not stenting is performedimmediately after this procedure to keep the artery open, antiplateletscan reduce the risk of forming additional blood clots following theprocedure(s).

Coronary bypass surgery is a surgical procedure in which an artery orvein is taken from elsewhere in the body and grafted to a blockedcoronary artery, rerouting blood around the blockage and through thenewly attached vessel. After the procedure, antiplatelets can reduce therisk of secondary blood clots.

Atrial fibrillation is the most common type of sustained irregular heartrhythm (arrhythmia). Atrial fibrillation affects about two millionAmericans every year. In atrial fibrillation, the atria (the heart'supper chambers) rapidly fire electrical signals that cause them toquiver rather than contract normally. The result is an abnormally fastand highly irregular heartbeat. When given after an episode of atrialfibrillation, antiplatelets can reduce the risk of blood clots formingin the heart and traveling to the brain (embolism).

There is evidence that a PGI2 receptor agonist will inhibit plateletaggregation and thus be a potential treatment as an antiplatelet therapy(see, e.g, Moncada et al, Lancet, 1977, 1:18-20). It has been shown thatgenetic deficiency of the PGI2 receptor in mice leads to an increasedpropensity towards thrombosis (Murata et al., Nature, 1997,388:678-682).

PGI2 receptor agonists can be used to treat, for example, claudicationor peripheral artery disease as well as cardiovascular complications,arterial thrombosis, atherosclerosis, vasoconstriction caused byserotonin, ischemia-reperfusion injury, and restenosis of arteriesfollowing angioplasty or stent placement. (See, e.g., Fetalvero et al.,Prostaglandins Other Lipid Mediat., 2007, 82:109-118; Arehart et al.,Curr. Med. Chem., 2007, 14:2161-2169; Davi et al., N. Engl. J. Med.,2007, 357:2482-2494; Fetalvero et al., Am. J. Physiol. Heart. Circ.Physiol., 2006, 290:H1337-H1346; Murata et al., Nature, 1997,388:678-682; Wang et al., Proc. Natl. Acad. Sci. USA, 2006,103:14507-14512; Xiao et al., Circulation, 2001, 104:2210-2215;McCormick et al., Biochem. Soc. Trans., 2007, 35:910-911; Arehart etal., Circ. Res., 2008, Mar. 6 Epub ahead of print.) PGI2 receptoragonists can also be used alone or in combination with thrombolytictherapy, for example, tissue-type plasminogen activator (t-PA), toprovide cardioprotection following MI or postischemic myocardialdysfunction or protection from ischemic injury during percutaneouscoronary intervention, and the like, including complications resultingtherefrom. PGI2 receptor agonists can also be used in antiplatelettherapies in combination with, for example, alpha-tocopherol (vitaminE), echistatin (a disintegrin) or, in states of hypercoagulability,heparin. (See, e.g., Chan., J. Nutr., 1998, 128:1593-1596; Mardla etal., Platelets, 2004, 15:319-324; Bernabei el al., Ann. Thorac.

Surg., 1995, 59:149-153; Gainza et al., J. Nephrol., 2006, 19:648-655.)The PGI2 receptor agonists disclosed herein provide beneficialimprovement in microcirculation to patients in need of antiplatelettherapy by antagonizing the vasoconstrictive products of the aggregatingplatelets in, for example and not limited to the indications describedabove. Accordingly, in some embodiments, the present invention providesmethods for reducing platelet aggregation in a patient in need thereof,comprising administering to the patient a composition comprising a PGI2receptor agonist disclosed herein. In further embodiments, the presentinvention provides methods for treating coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, or a symptom of any of the foregoing in a patient in needof the treatment, comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein.

In further embodiments, the present invention provides methods forreducing risk of blood clot formation in an angioplasty or coronarybypass surgery patient, or a patient suffering from atrial fibrillation,comprising administering to the patient a composition comprising a PGI2receptor agonist disclosed herein at a time where such risk exists.

3. Atherosclerosis

Atherosclerosis is a complex disease characterized by inflammation,lipid accumulation, cell death and fibrosis. It is the leading cause ofmortality in many countries, including the United States.Atherosclerosis, as the term is used herein, shall be understood toencompass disorders of large and medium-sized arteries that result inthe progressive accumulation within the intima of smooth muscle cellsand lipids.

It has been shown that an agonist of the PGI2 receptor can conferprotection from atherosclerosis, such as from atherothrombosis (Arehartet al., Curr. Med. Chem., 2007, 14:2161-2169; Stitham et al.,Prostaglandins Other Lipid Mediat., 2007, 82:95-108; Fries et al.,Hematology Am. Soc. Hematol. Educ. Program, 2005, 445-451; Egan et al.,Science, 2004, 306:1954-1957; Kobayashi et al., J. Clin. Invest., 2004,114:784-794: Arehart et al., Circ. Res., 2008, Mar. 6 Epub ahead ofprint).

It has been shown that defective PGI2 receptor signaling appears toaccelerate atherothrombosis in humans, i.e. that an agonist of the PGI2receptor can confer protection from atherothrombosis in humans (Arehartet al., Circ. Res., 2008, Mar. 6 Epub ahead of print).

The compounds of the present invention disclosed herein are useful inthe treatment of atherosclerosis, and the treatment of the symptomsthereof. Accordingly, in some embodiments, the present inventionprovides methods for treating atherosclerosis in a patient in need ofthe treatment, comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein. In furtherembodiments, methods are provided for treating a symptom ofatherosclerosis in a patient in need of the treatment, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein.

4. Asthma

Asthma is a lymphocyte-mediated inflammatory airway disordercharacterized by airway eosinophilia, increased mucus production bygoblet cells, and structural remodeling of the airway wall. Theprevalence of asthma has dramatically increased worldwide in recentdecades. It has been shown that genetic deficiency of the PGI2 receptorin mice augments allergic airway inflammation (Takahashi et al., Br JPharmacol, 2002, 137:315-322). It has been shown that an agonist of thePGI2 receptor can suppress not only the development of asthma when givenduring the sensitization phase, but also the cardinal features ofexperimental asthma when given during the challenge phase (Idzko et al.,J. Clin. Invest, 2007, 117:464472; Nagao et al., Am. J. Respir. CellMol. Biol., 2003, 29:314-320), at least in part through markedlyinterfering with the function of antigen-presenting dendritic cellswithin the airways (Idzko et al., J. Clin. Invest. 2007, 117:464-472;Zhou et al., J. Immunol., 2007, 178:702-710; Jaffar et al., J. Immunol.,2007, 179:6193-6203; Jozefowski et al., int. Immunopharmacol., 2003,3:865-878). These cells are crucial for both the initiation and themaintenance phases of allergic asthma, as depletion of airway dendriticcells during secondary challenge in sensitized mice abolished allcharacteristic features of asthma, an effect that could be completelyrestored by adoptive transfer of wild-type dendritic cells (van Rijt etal., J. Exp. Med., 2005, 201:981-991). It has also been shown that anagonist of the PGI2 receptor can inhibit proinflammatory cytokinesecretion by human alveolar macrophages (Raychauhuri et al., J. Biol.Chem., 2002, 277:33344-33348). The compounds of the present inventiondisclosed herein are useful in the treatment of asthma, and thetreatment of the symptoms thereof. Accordingly, in some embodiments, thepresent invention provides methods for treating asthma in a patient inneed of the treatment, comprising administering to the patient acomposition comprising a PGI2 receptor agonist disclosed herein. Infurther embodiments, methods are provided for treating a symptom ofasthma in a patient in need of the treatment, comprising administeringto the patient a composition comprising a PGI2 receptor agonistdisclosed herein.

5. Diabetic-Related Pathologies

Although hyperglycemia is the major cause for the pathogenesis ofdiabetic complications such as diabetic peripheral neuropathy (DPN),diabetic nephropathy (DN) and diabetic retinopathy (DR), enhancedvasoconstriction and platelet aggregation in diabetic patients has alsobeen implicated to play a role in disease progression (Cameron et al.,Naunyn Schmiedebergs Arch. Pharmacol., 2003, 367:607-614). Agonists ofthe PGI2 receptor promote vasodilation and inhibit platelet aggregationImproving microvascular blood flow is able to benefit diabeticcomplications (Cameron, Diabetologia, 2001, 44:1973-1988).

It has been shown that an agonist of the PGI2 receptor can prevent andreverse motor and sensory peripheral nerve conduction abnormalities instreptozotocin-diabetic rats (Cotter et al., Naunyn Schmiedebergs Arch.Pharmacol., 1993, 347:534-540). Further evidence for the beneficialeffect of an agonist of the PGI2 receptor in the treatment of diabeticperipheral neuropathy is given by Hotta et al. (Diabetes, 1996,45:361-366), Ueno et al. (Jpn. J. Pharmacol., 1996, 70:177-182), Ueno etal. (Life Sci., 1996, 59:PL105-PL110), Hotta el al. (Prostaglandins,1995, 49:339-349), Shindo et al. (Prostaglandins, 1991, 41:85-96), Okudaet al. (Prostaglandins, 1996, 52:375-384), and Koike et al. (FASEB J.,2003, 17:779-781). Evidence for the beneficial effect of an agonist ofthe PGI2 receptor in the treatment of diabetic nephropathy is given byOwada et al. (Nephron, 2002, 92:788-796) and Yamashita et al. (DiabetesRes. Clin. Pract., 2002, 57:149-161). Evidence for the beneficial effectof an agonist of the PGI2 receptor in the treatment of diabeticretinopathy is given by Yamagishi et al. (Mol. Med., 2002, 8:546-550),Burnette et al. (Exp. Eye Res., 2006, 83:1359-1365), and Hotta et al.(Diabetes, 1996, 45:361-366). It has been shown that an agonist of thePGI2 receptor can reduce increased tumor necrosis factor-α (TNF-α)levels in diabetic patients, implying that an agonist of the PGI2receptor may contribute to the prevention of progression in diabeticcomplications (Fujiwam et al., Exp. Clin. Endocrinol. Diabetes, 2004,112:390-394).

6. Glaucoma

Evidence that topical administration of an agonist of the PGI2 receptorcan result in a decrease in intraocular pressure (IOP) in rabbits anddogs and thereby have beneficial effect in the treatment of glaucoma isgiven by Hoyng et al. (Hoyng et al., Invest. Ophthalmol. Vis. Sci.,1987, 28:470-476).

7. Hypertension

Agonists of the PGI2 receptor have been shown to have activity forregulation of vascular tone, for vasodilation, and for amelioration ofpulmonary hypertension (see, e.g., Strauss et al., Clin Chest Med, 2007,28:127-142; Driscoll et al., Expert Opin. Pharmacother., 2008, 9:65-81).Evidence for a beneficial effect of an agonist of the PGI2 receptor inthe treatment of hypertension is given by Yamada et al. (Peptides, 2008,29:412-418). Evidence that an agonist of the PGI2 receptor can protectagainst cerebral ischemia is given by Dogan et al. (Gen. Pharmacol.,1996, 27:1163-1166) and Fang et al. (J. Cereb. Blood Flow Metab., 2006,26:491-501).

8. Anti-Inflammation Therapies

Anti-inflammation agents are prescribed for a variety of conditions. Forexample, in an inflammatory disease they are used to interfere with andthereby reduce an underlying deleterious There is evidence that a PGI2receptor agonist can inhibit inflammation and thus be a potentialtreatment as an anti-inflammation therapy. It has been shown that anagonist of the PGI2 receptor can inhibit pro-inflammatory cytokine andchemokine (interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α),IL-1α, IL-6, macrophage inflammatory protein-1alpha (MIP-1α), monocytechemoattractant protein-1 (MCP-1)) production and T cell stimulatoryfunction of dendritic cells (Jozefowski et al., Int. Immunopharmacol.,2003, 865-878; Zhou el al., J. Immunol., 2007, 178:702-710; Nagao elal., Am. J. Respir. Cell Mol. Biol., 2003, 29:314-320, Idzko et al., J.Clin. Invest., 2007, 117:464-472). It has been shown that an agonist ofthe PGI2 receptor can inhibit pro-inflammatory cytokine (TNF-α, IL-1β,IL-6, granulocyte macrophage stimulating factor (GM-CSF)) production bymacrophages (Raychaudhuri et al., J. Biol. Chem., 2002, 277:33344-33348;Czeslick et al., Eur. J. Clin. Invest., 2003, 33:1013-1017; Di Renzo etal., Prostaglandin Leukot. Essent. Fatty Acids, 2005, 73:405-410;Shinomiya et al., Biochem. Pharmacol., 2001, 61:1153-1160). It has beenshown that an agonist of the PGI2 receptor can stimulateanti-inflammatory cytokine (IL-10) production by dendritic cells(Jozefowski et al., Int. Immunophanmacol., 2003, 865-878; Zhou et al.,J. Immunol., 2007, 178:702-710). It has been shown that an agonist ofthe PGI2 receptor can stimulate anti-inflammatory cytokine (IL-10)production by macrophages (Shinomiya et al., Biochem. Pharmacol., 2001,61:1153-1160). It has been shown that an agonist of the PGI2 receptorcan inhibit a chemokine (CCL17)-induced chemotaxis of leukocytes(CD4⁺≥Th2 T cells) (Jaffar et al., J. Immunol., 2007, 179:6193-6203). Ithas been shown that an agonist of the PGI2 receptor can conferprotection from atherosclerosis, such as from atherothrombosis (Arehartet al., Curr. Med. Chem., 2007, 14:2161-2169; Stitham el al.,Prostaglandins Other Lipid Mediat., 2007, 82:95-108; Fries et al.,Hematology Am. Soc. Hematol. Educ. Program, 2005, 445-451; Egan et al.,Science, 2004, 306:1954-1957; Kobayashi et al., J. Clin. Invest., 2004,114:784-794; Arehart et al., Circ. Res., 2008, Mar. 6 Epub ahead ofprint). It has been shown that an agonist of the PGI2 receptor canattenuate asthma (Idzko et al., J. Clin. Invest., 2007, 117:464-472;Jaffar et al., J. Immunol., 2007, 179:6193-6203; Nagao et al., Am. J.Respir. Cell. Mol. Biol., 2003, 29:314-320). It has been shown that anagonist of the PGI2 receptor can decrease TNF-α production in type 2diabetes patients (Fujiwara et al., Exp. Clin. Endocrinol. Diabetes,2004, 112:390-394; Goya et al., Metabolism, 2003, 52:192-198). It hasbeen shown that an agonist of the PGI2 receptor can inhibitischemia-reperfusion injury (Xiao et al., Circulation, 2001,104:2210-2215). It has been shown that an agonist of the PGI2 receptorcan inhibit restenosis (Cheng et al., Science, 2002, 296:539-541). Ithas been shown that an agonist of the PGI2 receptor can attenuatepulmonary vascular injury and shock in a rat model of septic shock(Harada et al., Shock, 2008, Feb. 21 Epub ahead of print). It has beenshown that an agonist of the PGI2 receptor can reduce the serum levelsof TNF-α in vivo in patients with rheumatoid arthritis, and this isassociated with improvement in the clinical course of the disease (Gaoet al., Rheumatol. Int., 2002, 22:45-51; Boehme et al., Rheumatol. Int.,2006, 26:340-347).

The compounds of the present invention disclosed herein providebeneficial reduction of inflammation. The compounds of the presentinvention disclosed herein provide beneficial reduction of a deleteriousinflammatory response associated with an inflammatory disease.Accordingly, in some embodiments, the present invention provides methodsfor reducing inflammation in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for decreasing IL-12, TNF-α, IL-1α, IL-1β, IL-6, MIP-1αor MCP-1 production in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for decreasing TNF-α production in a patient in needthereof, comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein. In someembodiments, the present invention provides methods for increasing IL-10production in a patient in need thereof, comprising administering to thepatient a composition comprising a PGI2 receptor agonist disclosedherein. In some embodiments, the present invention provides methods forreducing a deleterious inflammatory response associated with aninflammatory disease in a patient in need thereof, comprisingadministering to the patient a composition comprising a PGI2 receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for treating an inflammatory disease or a symptomthereof in a patient in need of the treatment comprising administeringto the patient a composition comprising a PGI2 receptor agonistdisclosed herein. In some embodiments, the present invention providesmethods for treating an inflammatory disease or a symptom thereof in apatient in need of the treatment comprising administering to the patienta composition comprising a PGI2 receptor agonist disclosed herein. Insome embodiments, the present invention provides methods for treating aninflammatory disease or a symptom thereof in a patient in need of thetreatment comprising administering to the patient a compositioncomprising a PGI2 receptor agonist disclosed herein, wherein theinflammatory disease is selected from the group consisting of psoriasis,psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplantrejection, multiple sclerosis, systemic lupus erythematosus (SLE),ulcerative colitis, ischemia-reperfusion injury, restenosis,atherosclerosis, acne, diabetes (including type 1 diabetes and type 2diabetes), sepsis, chronic obstructive pulmonary disease (COPD), andasthma.

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds as described herein andone or more pharmaceutically acceptable carriers. The embodimentspertain to pharmaceutical compositions comprising a compound of thepresent invention and a pharmaceutically acceptable carrier.

The embodiments of the present invention include a method of producing apharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations maybe in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20^(th) Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro et al.)

While it is possible that, for use in the prophylaxis or treatment, acompound of the invention may, in an alternative use, be administered asa raw or pure chemical, it is preferable however to present the compoundor active ingredient as a pharmaceutical formulation or compositionfurther comprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt, solvate, hydrate or derivative thereof together with one or morepharmaceutically acceptable carriers thereof and/or prophylacticingredients. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and not overlydeleterious to the recipient thereof. Typical procedures for making andidentifying suitable hydrates and solvates, outside those mentionedherein, are well known to those in the art; see for example, pages202-209 of K. J. Guillory, “Generation of Polymorphs, Hydrates,Solvates, and Amorphous Solids,” in: Polymorphism in PharmaceuticalSolids, ed. Harry G. Brittan, Vol. 95, Marcel Dekker, Inc., New York,1999, incorporated herein by reference in its entirety.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate, hydrate orphysiologically functional derivative thereof can be used as activeingredients in pharmaceutical compositions, specifically as PGI2receptor modulators. By the term “active ingredient” is defined in thecontext of a “pharmaceutical composition” and is intended to mean acomponent of a pharmaceutical composition that provides the primarypharmacological effect, as opposed to an “inactive ingredient” whichwould generally be recognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits and as is customary and is known to the physician, itis to be tailored to the individual conditions in each individual case.It depends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention. Representative dosesof the present invention include, but not limited to, about 0.001 mg toabout 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about25 mg. Multiple doses may be administered during the day, especiallywhen relatively large amounts are deemed to be needed, for example 2, 3or 4 doses. Depending on the individual and as deemed appropriate fromthe patient's physician or caregiver it may be necessary to deviateupward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, on whether anacute or chronic disease state is being treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4 part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt, solvate or hydrate of a compound ofthe invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcelluose, sodium carboxymethylcellulose, alow melting wax, cocoa butter and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents and thelike.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the present invention as an aerosol can be prepared byprocesses well known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the compounds ofthe present invention in water, water/alcohol mixtures or suitablesaline solutions can be employed using customary additives, for examplebenzyl alcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and othersand, if appropriate, customary propellants, for example include carbondioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane,or dichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, oxalic, p-toluenesulfonic and the like. Certain compounds ofthe present invention which contain a carboxylic acid functional groupmay optionally exist as pharmaceutically acceptable salts containingnon-toxic, pharmaceutically acceptable metal cations and cations derivedfrom organic bases. Representative metals include, but are not limitedto, aluminium, calcium, lithium, magnesium, potassium, sodium, zinc andthe like. In some embodiments the pharmaceutically acceptable metal issodium. Representative organic bases include, but are not limited to,benzathine (N¹,N²-dibenzylethane-1,2-diamine), chloroprocaine(2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline,diethanolamine, ethylenediamine, meglumine((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine(2-(diethylamino)ethyl 4-aminobenzoate), and the like. Certainpharmaceutically acceptable salts are listed in Berge, et al., Journalof Pharmaceutical Sciences, 66:1-19 (1977), incorporated herein byreference in its entirety.

The embodiments of the present invention include every combination ofone or more compounds selected from the following group andpharmaceutically acceptable solvates and hydrates thereof:

-   sodium    2-(((1r,4r)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate;-   sodium    2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate;-   sodium    2-(((1r,4r)-4-(((4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methmy)acetate:-   sodium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoy)acetate:-   magnesium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methaxy)acetate;-   potassium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methaxy)acetate;    and-   calcium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoaxy)acetate.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compounds of the present invention can be converted to “pro-drugs.” Theterm “pro-drugs” refers to compounds that have been modified withspecific chemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T Higuchi and V.Stella. Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

The embodiments of the present invention include a method of producing apharmaceutical composition for “combination-therapy” comprising admixingat least one compound according to any of the compound embodimentsdisclosed herein, together with at least one known pharmaceutical agentas described herein and a pharmaceutically acceptable carrier.

It is noted that when the PGI2 receptor modulators are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as PGI2receptor modulators, for the treatment of an PGI2-associated disease ordisorder in companionship animals (e.g., cats, dogs, etc.) and inlivestock animals (e.g., cows, chickens, fish, etc.) Those of ordinaryskill in the art are readily credited with understanding the utility ofsuch compounds in such settings.

Hydrates and Solvates

It is understood that when the phrase “pharmaceutically acceptablesalts, solvates and hydrates” is used in reference to a particularformula herein, it is intended to embrace solvates and/or hydrates ofcompounds of the particular formula, pharmaceutically acceptable saltsof compounds of the particular formula as well as solvates and/orhydrates of pharmaceutically acceptable salts of compounds of theparticular formula. It is also understood by a person of ordinary skillin the art that hydrates are a subgenus of solvates.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be apparent tothose skilled in the art that the following dosage forms may comprise,as the active component, either a compound of the invention or apharmaceutically acceptable salt or as a solvate or hydrate thereof.Moreover, various hydrates and solvates of the compounds of theinvention and their salts will find use as intermediates in themanufacture of pharmaceutical compositions. Typical procedures formaking and identifying suitable hydrates and solvates, outside thosementioned herein, are well known to those in the art; see for example,pages 202-209 of K. J. Guillorv, “Generation of Polymorphs, Hydrates.Solvates, and Amorphous Solids,” in: Polymorphism in PharmaceuticalSolids, ed. Harry G. Brittan, Vol. 95. Marcel Dekker, Inc., New York,1999, incorporated herein by reference in its entirety. Accordingly, oneaspect of the present invention pertains to hydrates and solvates ofcompounds of the present invention and/or their pharmaceuticalacceptable salts, as described herein, that can be isolated andcharacterized by methods known in the art, such as, thermogravimetricanalysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powderX-ray diffraction (PXRD), Karl Fisher titration, high resolution X-raydiffraction, and the like. There are several commercial entities thatprovide quick and efficient services for identifying solvates andhydrates on a routine basis. Example companies offering these servicesinclude Wilmington PharmaTech (Wilmington, Del.). Avantium Technologies(Amsterdam) and Aptuit (Greenwich, Conn.).

The embodiments of the present invention include every combination ofone or more solvate or hydrate selected from the following group:

-   sodium    2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate    hydrate;-   sodium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate    hydrate;-   magnesium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methaxy)acetateisopropanol    solvate;-   potassium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methaxy)acetate    isopropanol solvate; and-   calcium    2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateisopropanol    solvate.

Certain solvates and hydrates of compounds of the present invention aredescribed in Examples 1.107 to 1.111.

Crystalline Forms

A further aspect of the present invention pertains to a crystalline form(Form 1) of sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy))methyl)cyclohexyl)methaxy)acetate(the sodium salt of Compound 22). Form 1 of the sodium salt of Compound22 can be identified by its unique solid state signature with respectto, for example, differential scanning calorimetry (DSC), X-ray powderdiffraction (PXRD), and other solid state methods. Furthercharacterization with respect to water or solvent content of thecrystalline form can be gauged by any of the following methods forexample, thermogravimetric analysis (TGA), DSC and the like. For DSC, itis known that the temperatures observed will depend upon sample purity,the rate of temperature change, as well as sample preparation techniqueand the particular instrument employed. Thus, the values reported hereinrelating to DSC thermograms can vary by plus or minus about 6° C. Thevalues reported herein relating to DSC thermograms can also vary by plusor minus about 20 joules per gram. For PXRD, the relative intensities ofthe peaks can vary, depending upon the sample preparation technique, thesample mounting procedure and the particular instrument employed.Moreover, instrument variation and other factors can often affect the2θvalues. Therefore, the peak assignments of diffraction patterns canvary by plus or minus about 0.2 °2θ. For TGA, the features reportedherein can vary by plus or minus about 5° C. The TGA features reportedherein can also vary by plus or minus about 2% weight change due to, forexample, sample variation. Further characterization with respect tohygroscopicity of the crystalline form can be gauged by, for example,dynamic vapor sorption (DVS). The DVS features reported herein can varyby plus or minus about 5% relative humidity. The DVS features reportedherein can also vary by plus or minus about 5% weight change. Thephysical properties of Form 1 of the sodium salt of Compound 22 aresummarized in Table 1 below.

TABLE 1 Sodium Salt of Compound 22 (Form 1) TGA FIG. 11: <0.1% weightloss below about 200° C. DSC FIG. 11: extrapolated onset temperature:243° C.; endotherm peak temperature: 245° C. (maximum); associated heatflow 105 J/g PXRD FIG. 9: Peaks of ≥10% relative intensity at 6.1, 7.5,9.6, 12.3, 14.5, 19.4, 20.0, 22.1, 23.1 and 23.9 °2θ DVS FIG. 10:absorption of <0.25% at 90% relative humidity

The small weight loss observed in the TGA data suggests that Form 1 ofthe sodium salt of Compound 22 is an anhydrous, non-solvated crystallineform. The DSC thermogram further reveals a melting endotherm with anonset at about 243° C.

DVS data for the crystalline form of the Form 1 of the sodium salt ofCompound 22 reveals low hygroscopicity, with absorption of less than0.25% at 90% relative humidity.

Certain X-ray powder diffraction peaks for Form 1 of the sodium salt ofCompound 22 are shown in Table 2 below.

TABLE 2 Sodium Salt of Compound 22 (Form 1) PXRD Peaks with RelativeIntensity of 10% or Higher (°2θ) Peak Position (°2θ) Relative Intensity(%) 6.1 65 7.5 32 9.6 11 12.3 14 14.5 15 19.4 27 20.0 100 22.1 29 23.116 23.9 31

One aspect of the present invention is directed to a crystalline form(Form 1) of sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamaylow)methyl)cyclohexyl)methaxy)acetatehaving an X-ray powder diffraction pattern comprising a peak, in termsof 2θ, at about 20.0. In some embodiments, the crystalline form has anX-ray powder diffraction pattern comprising a peak, in terms of 2θ, atabout 6.1°. In some embodiments, the crystalline form has an X-raypowder diffraction pattern comprising a peak, in terms of 2θ, at about20.0° and about 6.1°. In some embodiments, the crystalline form has anX-ray powder diffraction pattern comprising a peak, in terms of 2θ, atabout 20.0° and about 7.5 In some embodiments, the crystalline form hasan X-ray powder diffraction pattern comprising a peak, in terms of 2θ,at about 20.0°, about 6.1° and about 7.5°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 20.0°, about 6.1°, about 7.5°, about23.9°, about 22.1°, about 19.4°, about 23.1° and about 14.5. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising a peak, in terms of 2θ, at about 20.0°, about 6.1°,about 7.5°, about 23.9°, about 22.1°, about 19.4°, about 23.1°, about14.5°, about 12.3° and about 9.6°. In yet further embodiments, thecrystalline form has an X-ray powder diffraction pattern substantiallyas shown in FIG. 9 , wherein by “substantially” is meant that thereported peaks can vary by about ±0.2 °2θ.

In some embodiments, the crystalline form (Form 1) of sodium24-((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclchexyl)methoxy)acetatehas a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature between about 235° C.and about 250° C. In some embodiments, the crystalline form has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature at about 243° C. In someembodiments, the crystalline form has a differential scanningcalorimetry thermogram comprising an endotherm with a peak temperaturebetween about 237° C. and about 252° C. In some embodiments, thecrystalline form has a differential scanning calorimetry thermogramcomprising an endotherm with a peak temperature at about 245° C. In someembodiments, the crystalline form has a differential scanningcalorimetry thermogram comprising an endotherm with an associated heatflow of about 105 joules per gram. In further embodiments, thecrystalline form has a differential scanning calorimetry thermogramsubstantially as shown in FIG. 11 , wherein by “substantially” is meantthat the reported DSC features can vary by about +4° C.

In some embodiments, the crystalline form (Form 1) of sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methvl)cyclohexvl)methoxy)acetatehas a dynamic vapor sorption profile substantially as shown in FIG. 10 ,wherein by “substantially” is meant that the reported DVS features canvary by about 5% relative humidity.

In some embodiments, the crystalline form (Form 1) of sodium24-((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclchexyl)methoxy)acetatehas a thermogravimetric analysis profile substantially as shown in FIG.11 , wherein by “substantially” is meant that the reported TGA featurescan vary by about ±5° C.

The crystalline form (Form 1) of sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate,the sodium salt of Compound 22 described herein, can be prepared by anyof the suitable procedures known in the art for preparing crystallinepolymorphs. In some embodiments Form 1 of the sodium salt of Compound 22can be prepared as described in Example 1.106. In some embodiments, Form1 of the sodium salt of Compound 22 can be prepared by heatingcrystalline sodium salt of Compound 22, containing one or morecrystalline forms other than Form 1. In some embodiments, Form 1 of thesodium salt of Compound 22 can be prepared by recrystallizingcrystalline sodium salt of Compound 22, containing one or morecrystalline forms other than Form 1 of the sodium salt of Compound 22.

A further aspect of the present invention pertains to a crystalline formof2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid (Compound 22). The crystalline form of Compound 22 of the presentinvention can be identified by its unique solid state signature withrespect to, for example, differential scanning calorimetry (DSC), X-raypowder diffraction (PXRD), and other solid state methods. Furthercharacterization with respect to water or solvent content of thecrystalline form can be gauged by any of the following methods forexample, thermogravimetric analysis (TGA), DSC and the like. For DSC, itis known that the temperatures observed will depend upon sample purity,the rate of temperature change, as well as sample preparation techniqueand the particular instrument employed. Thus, the values reported hereinrelating to DSC thermograms can vary by plus or minus about 6° C. Thevalues reported herein relating to DSC thermograms can also vary by plusor minus about 20 joules per gram. For PXRD, the relative intensities ofthe peaks can vary, depending upon the sample preparation technique, thesample mounting procedure and the particular instrument employed.Moreover, instrument variation and other factors can often affect the2θvalues. Therefore, the peak assignments of diffraction patterns canvary by plus or minus about 0.2° 2. For TGA, the features reportedherein can vary by plus or minus about 5° C. The TGA features reportedherein can also vary by plus or minus about 2% weight change due to, forexample, sample variation. Further characterization with respect tohygroscopicity of the crystalline form can be gauged by, for example,dynamic vapor sorption (DVS). The physical properties of the crystallineform of Compound 22 of the present invention are summarized in Table 3below.

TABLE 3 Crystalline form of Compound 22 TGA FIG. 26: Insignificantweight loss below about 128° C. DSC FIG. 26: extrapolated onsettemperature: 128° C.; endotherm peak temperature: 129° C. (maximum);associated heat flow 109 J/g PXRD FIG. 27: Peaks of ≥8% relativeintensity at 8.9, 10.8, 11.9, 15.2, 16.4, 16.9, 18.9, 20.3, 20.7 and21.5 °2θ

The insignificant weight loss observed in the TGA data suggests that thecrystalline form of Compound 22 of the present invention is ananhydrous, non-solvated crystalline form. The DSC thermogram furtherreveals a melting endotherm with an onset at about 128° C.

Certain X-ray powder diffraction peaks for the crystalline form ofCompound 22 of the present invention are shown in Table 4 below.

TABLE 4 Compound 22 Crystalline Form PXRD Peaks with Relative Intensityof 8% or Higher (°2θ) Peak Position (°2θ) Relative Intensity (%) 8.9 810.8 19 11.9 29 15.2 9 16.4 49 16.8 63 18.9 84 20.3 34 20.7 62 21.5 100

One aspect of the present invention is directed to a crystalline form of2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid having an X-ray powder diffraction pattern comprising a peak, interms of 2θ, at about 21.5. In some embodiments, the crystalline formhas an X-ray powder diffraction pattern comprising a peak, in terms of2θ, at about 18.9°. In some embodiments, the crystalline form has anX-ray powder diffraction pattern comprising a peak, in terms of 2θ, atabout 21.5° and about 18.9°. In some embodiments, the crystalline formhas an X-ray powder diffraction pattern comprising a peak, in terms of2θ, at about 21.5° and about 20.7°. In some embodiments, the crystallineform has an X-ray powder diffraction pattern comprising a peak, in termsof 2θ, at about 21.5°, about 18.9°, and about 20.7°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising a peak, in terms of 2θ, at about 21.5°, about 18.9°,about 20.7° about 16.9°, about 16.4°, about 20.3° about 1.9° and about10.8. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising a peak, in terms of 2θ, at about 18.9°,about 20.7°, about 16.9°, about 16.4°, about 20.3°, about 11.9° about10.8°, about 15.2° and about 8.9°. In yet further embodiments, thecrystalline form has an X-ray powder diffraction pattern substantiallyas shown in FIG. 27 , wherein by “substantially” is meant that thereported peaks can vary by about ±0.2 °2θ.

In some embodiments, the crystalline form of2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid has a differential scanning calorimetry thermogram comprising anendotherm with an extrapolated onset temperature between about 120° C.and about 135° C. In some embodiments, the crystalline form has adifferential scanning calorimetry thermogram comprising an endothermwith an extrapolated onset temperature at about 128° C. In someembodiments, the crystalline form has a differential scanningcalorimetry thermogram comprising an endotherm with a peak temperaturebetween about 121° C. and about 136° C. In some embodiments, thecrystalline form has a differential scanning calorimetry thermogramcomprising an endotherm with a peak temperature at about 129° C. In someembodiments, the crystalline form has a differential scanningcalorimetry thermogram comprising an endotherm with an associated heatflow of about 109 joules per gram. In further embodiments, thecrystalline form has a differential scanning calorimetry thermogramsubstantially as shown in FIG. 26 , wherein by “substantially” is meantthat the reported DSC features can vary by about 4° C.

In some embodiments, the crystalline form of2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid has a thermogravimetric analysis profile substantially as shown inFIG. 28 , wherein by “substantially” is meant that the reported TGAfeatures can vary by about ±5° C.

The crystalline form of2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)metylw)cycldhexyl)methoxy)aceticacid, Compound 22, described herein, can be prepared by any of thesuitable procedures known in the art for preparing crystallinepolymorphs. In some embodiments the crystalline form of Compound 22 ofthe present invention can be prepared as described in Example 1.115. Insome embodiments, the crystalline form of Compound 22 of the presentinvention can be prepared by heating crystalline Compound 22, containingone or more crystalline forms other than the crystalline form ofCompound 22 of the present invention. In some embodiments, thecrystalline form of Compound 22 of the present invention can be preparedby recrystallizing crystalline Compound 22, containing one or morecrystalline forms other than the crystalline form of Compound 22 of thepresent invention.

Compositions Containing Crystalline Forms of the Present Invention

The present invention further provides compositions containing thecrystalline form (Form 1) of sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate,the sodium salt of Compound 22 described herein.

In some embodiments, the compositions of the invention include at leastabout 1, about 5, about 10, about 20, about 30, or about 40% by weightof Form 1 of the sodium salt of Compound 22.

In some embodiments, the compositions of the invention include at leastabout 50, about 60, about 70, about 80, about 90, about 95, about 96,about 97, about 98, or about 99% by weight of Form 1 of the sodium saltof Compound 22.

In some embodiments, compositions of the invention include Form 1 of thesodium salt of Compound 22 and a pharmaceutically acceptable carrier.

The present invention further provides compositions containing thecrystalline form of2-(((1r,4r)-4-(((4-chlorophenyl)(phenvl)carbamayloxy)methyl)cyclohexyl)methax)aceticacid,Compound 22, described herein.

In some embodiments, the compositions of the invention include at leastabout 1, about 5, about 10, about 20, about 30, or about 40% by weightof the crystalline form of Compound 22 of the present invention.

In some embodiments, the compositions of the invention include at leastabout 50, about 60, about 70, about 80, about 90, about 95, about 96,about 97, about 98, or about 99% by weight of the crystalline form ofCompound 22 of the present invention.

In some embodiments, compositions of the invention include thecrystalline form of Compound 22 of the present invention and apharmaceutically acceptable carrier.

Processes of the Present Invention

The present invention is directed, inter alia, to processes andintermediates for the preparation of cyclohexane derivatives that areuseful in the treatment of: pulmonary arterial hypertension (PAH);idiopathic PAH; familial PAH; PAH associated with: a collagen vasculardisease, a congenital heart disease, portal hypertension, HIV infection,ingestion of a drug or toxin, hereditary hemorrhagic telangiectasia,splenectomy, pulmonary veno-occlusive disease (PVOD) or pulmonarycapillary hemangiomatosis (PCH); PAH with significant venous orcapillary involvement; platelet aggregation; coronary artery disease;myocardial infarction; transient ischemic attack; angina; stroke;ischemia-reperfusion injury; restenosis; atrial fibrillation; blood clotformation in an angioplasty or coronary bypass surgery individual or inan individual suffering from atrial fibrillation; atherothrombosis;asthma or a symptom thereof; a diabetic-related disorder such asdiabetic peripheral neuropathy, diabetic nephropathy or diabeticretinopathy; glaucoma or other disease of the eye with abnormalintraocular pressure; hypertension; inflammation; psoriasis; psoriaticarthritis; rheumatoid arthritis; Crohn's disease; transplant rejection;multiple sclerosis; systemic lupus erythematosus (SLE); ulcerativecolitis; atherosclerosis; acne; type 1 diabetes; type 2 diabetes;sepsis; and chronic obstructive pulmonary disorder (COPD).

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography.

In some embodiments, preparation of compounds can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Greene and Wuts,Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, 1999,which is incorporated herein by reference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected. In some embodiments, reactionscan be carried out in the absence of solvent, such as when at least oneof the reagents is a liquid or gas.

Suitable solvents can include halogenated solvents such as carbontetrachloride, bromodichloromethane, dibromochloromethane, bromoform,chloroform, bromochloromethane, dibromomethane, butyl chloride,dichloromethane, tetrachloroethylene, trichloroethylene,1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane,2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene,o-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane,chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride,dichlorofluoromethane, chlorodifluoromethane, trifluoromethane,1,2-dichlorotetrafluorethane and hexafluoroethane.

Suitable ether solvents include: dimethoxymethane, tetrahydrofuran,1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,diethylene glycol diethyl ether, triethylene glycol dimethyl ether,anisole, or t-butyl methyl ether.

Suitable protic solvents can include, by way of example and withoutlimitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol,2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol,2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butylalcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethylether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,phenol, or glycerol.

Suitable aprotic solvents can include, by way of example and withoutlimitation, tetrahydrofuran, N,N-dimethylformamide.N,N-dimethylacetamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidinone, formamide,N-methylacetamide. N-methylformamide, acetonitrile, dimethyl sulfoxide,propionitrile, ethyl formate, methyl acetate, hexachloroacetone,acetone, ethyl methyl ketone, ethyl acetate, sulfolane,N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene,or hexamethylphosphoramide.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane,hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene,o, m-, or p-xylene, octane, indane, nonane, or naphthalene.

Supercritical carbon dioxide can also be used as a solvent.

The reactions of the processes described herein can be carried out atappropriate temperatures which can be readily determined by one skilledin the art. Reaction temperatures will depend on, for example, themelting and boiling points of the reagents and solvent, if present; thethermodynamics of the reaction (e.g., vigorously exothermic reactionsmay need to be carried out at reduced temperatures); and the kinetics ofthe reaction (e.g., a high activation energy barrier may need elevatedtemperatures).

The reactions of the processes described herein can be carried out inair or under an inert atmosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto one skilled in the art.

In some embodiments, preparation of compounds can involve the additionof acids or bases to effect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids. Inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, andnitric acid. Organic acids include formic acid, acetic acid, propionicacid, butanoic acid, methanesulfonic acid, p-toluene sulfonic acid,benzenesulfonic acid, propiolic acid, butyric acid, 2-butynoic acid,vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid,octanoic acid, nonanoic acid and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, and potassium carbonate.Some example strong bases include, but are not limited to, hydroxide,alkoxides, metal amides, metal hydrides, metal dialkylamides andarylamines, wherein; alkoxides include lithium, sodium and potassiumsalts of methyl, ethyl and t-butyl oxides; metal amides include sodiumamide, potassium amide and lithium amide; metal hydrides include sodiumhydride, potassium hydride and lithium hydride; and metal dialkylamidesinclude sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis.

The processes described herein can be stereoselective such that anygiven reaction starting with one or more chiral reagents enriched in onestereoisomer forms a product that is also enriched in one stereoisomer.The reaction can be conducted such that the product of the reactionsubstantially retains one or more chiral centers present in the startingmaterials. The reaction can also be conducted such that the product ofthe reaction contains a chiral center that is substantially invertedrelative to a corresponding chiral center present in the startingmaterials.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization (for example, diastereomeric salt resolution) using a“chiral resolving acid” which is an optically active, salt-formingorganic acid. Suitable resolving agents for fractional recrystallizationmethods are, for example, optically active acids, such as the D and Lforms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid or the various optically activecamphorsulfonic acids such as β-camphorsulfonic acid. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of β-methylbenzylamine (e.g., S and Rforms, or diastereomerically pure forms), 2-phenylglycinol,norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers. Tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution.

Upon carrying out preparation of compounds according to the processesdescribed herein, the usual isolation and purification operations suchas concentration, filtration, extraction, solid-phase extraction,recrystallization, chromatography, and the like may be used, to isolatethe desired products.

Example processes and certain intermediates of the present invention,are shown in Scheme I below, wherein each substituent of the compoundsdepicted are defined herein.

One aspect of the present invention pertains to processes, such as thatexemplified by Scheme I (supra), that involve compounds of Formulae(II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) or salt formsthereof, wherein:

R¹ is selected from C₁-C₆ alkyl, aryl and heteroaryl; each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R² is selected from: H, C₁-C₆ alkyl and aryl; wherein said aryl isoptionally substituted with one or two substituents selected from: C₁-C₆alkyl and halogen;

R⁵ is C₁-C₆ alkyl;

R⁶ is selected from: C₁-C₆ alkylarylsulfonate, C₁-C₆ alkylsulfonate,arylsulfonate, C₁-C₆ haloalkylsulfonate and halogen;

R⁷ is a first leaving group;

R⁸ is a second leaving group; and

M⊕ is a metal cation or a cation derived from an organic base.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g, R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and M) contained within the generic chemicalformulae described herein, for example, (II), (III), (IV), (V), (VI),(VII), (VIII) and (IX) are specifically embraced by the presentinvention just as if each and every combination was individuallyexplicitly recited, to the extent that such combinations embracecompounds that result in stable compounds (i.e., compounds that can beisolated, characterized and tested for biological activity).

Hydrolysis Step

The present invention provides, inter aka, processes for preparingcompounds of Formula (U):

or a salt, solvate or hydrate thereof; comprising reacting a compound ofFormula (III):

or a salt form thereof; with a hydrolyzing agent to form a compound ofFormula (II) or a salt form thereof.

In some embodiments, R¹ is aryl, optionally substituted with one or twosubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ allyl, aryl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is aryl, optionally substituted with F or Cl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R² is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R² is phenyl.

In some embodiments, R⁵ is tert-butyl.

In some embodiments, R¹ is 4-chlorophenyl; R² is phenyl; and R⁵ isTeri-butyl.

In some embodiments, R¹ is 3-fluorophenyl; R² is phenyl; and R⁵ isJeri-butyl.

The hydrolyzing agent can be any suitable reagent, readily selected byone skilled in the art. Examples of hydrolyzing agents include basessuch as lithium hydroxide and sodium hydroxide; acids such ashydrochloric acid, trifluoroacetic acid and formic acid; lithium saltssuch as LiBr, LiCl, LiBF₄, LiCF₃CO₂, LiSO₄, LiNO₃, LiCF₃SO₃ and lithiumpropanethiolate; and electrophiles such as TMSI.

In some embodiments, the hydrolyzing agent is a base.

In some embodiments, the hydrolyzing agent is an alkali metal hydroxide.

In some embodiments, the hydrolyzing agent is sodium hydroxide.

The reacting of a compound of Formula (III) with a hydrolyzing agent canbe optionally carried out in the presence of any suitable solvent,readily selected by one skilled in the art. Example solvents includepolar to moderately polar solvents or high boiling solvents such asN,N-dimethylformamide (DMF), N,N-dimethylacetamide, toluene,acetonitrile, propionitrile, tetrahydrofuran and N-methylpyrrolidinone.

In some embodiments, the solvent comprises toluene.

In some embodiments, the solvent comprises a mixture of toluene andwater.

In some embodiments, the solvent comprises a mixture of approximatelyequal parts by weight of toluene and water.

The reacting of a compound of Formula (III) with a hydrolyzing agent canbe carried out at any suitable temperature, readily selected by oneskilled in the art.

In some embodiments, the reacting is carried out at a temperature ofabout 20° C. to about 90° C.

In some embodiments, the reacting is carried out at a temperature ofabout 30° C. to about 80° C.

In some embodiments, the reacting is carried out at a temperature ofabout 40° C. to about 70° C.

In some embodiments, the reacting is carried out at a temperature ofabout 50° C. to about 60° C.

The reacting of a compound of Formula (III) with a hydrolyzing agent canbe optionally carried out in situ following the reacting of a compoundof Formula (IV) with a compound of Formula (V) in the presence of a baseto form a compound of Formula (III), without substantial purification ofthe compound of Formula (III).

Alkylation Step

The present invention further provides processes for preparing compoundsof Formula (iii):

or a salt form thereof; wherein:

R¹ is selected from C₁-C₆ alkyl, aryl and heteroaryl; each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R² is selected from: H, C₁-C₆ allyl and aryl; wherein said aryl isoptionally substituted with one or two substituents selected from: C₁-C₆alkyl and halogen; and

R⁵ is C₁-C₆ alkyl;

comprising reacting a compound of Formula (IV):

or a salt form thereof; with a compound of Formula (V):

wherein:

R⁶ is selected from: C₁-C₆ alkylarylsulfonate, C₁-C₆ alkylsulfonate,arylsulfonate, C₁-C₆ haloalkylsulfonate and halogen:

In the presence of a base to form a compound of Formula (III) or a saltform thereof.

In some embodiments, R¹ is aryl, optionally substituted with one or twosubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is aryl, optionally substituted with F or Cl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R² is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R¹ is phenyl.

In some embodiments, R⁵ is tert-butyl.

In some embodiments, R⁶ is halogen.

In some embodiments, R⁶ is bromo.

In some embodiments, R¹ is 4-chlorophenyl; R² is phenyl; R⁵ istert-butyl; and R⁶ is bromo.

In some embodiments, R¹ is 3-fluorophenyl; R² is phenyl; R⁵ istert-butyl; and R⁶ is bromo.

The base can be any suitable base, readily selected by one skilled inthe art. Examples of suitable bases include inorganic bases such asammonia and carbonates, hydroxides and hydrogen carbonates of metalssuch as sodium, potassium, magnesium, calcium, cesium and the like; andorganic bases such as methylamine, triethylamine,N-ethyldiisopropylamine, benzylamine, dibenzylamine, morpholine andpyridine.

In some embodiments, the base is an alkali metal hydroxide.

In some embodiments, the base is sodium hydroxide.

The reacting of a compound of Formula (IV) with a compound of Formula(V) can be optionally carried out in the presence of a catalyst.

In some embodiments, the catalyst is a phase-transfer catalyst.

In some embodiments, the catalyst is a tetraalkylammonium salt.

In some embodiments, the catalyst is a tetra-n-butylammonium bromide.

In some embodiments the molar ratio of the compound of Formula (IV) tothe catalyst is about 20:1 to about 0.5:1.

In some embodiments the molar ratio of the compound of Formula (IV) tothe catalyst is about 10:1 to about 1:1.

In some embodiments the molar ratio of the compound of Formula (IV) tothe catalyst is about 5:1 to about 2:1.

In some embodiments the molar ratio of the compound of Formula (IV) tothe catalyst is about 4:1 to about 3:1.

The reacting of a compound of Formula (IV) with a compound of Formula(V) can be optionally carried out in the presence of any suitablesolvent, readily selected by one skilled in the art. Example solventsinclude polar to moderately polar solvents or high boiling solvents suchas N,N-dimethylformamide (DMF), N,N-dimethylacetamide, toluene,acetonitrile, propionitrile, tetrahydrofuran and N-methylpyrrolidinone.

In some embodiments, the solvent comprises toluene.

In some embodiments, the solvent comprises a mixture of toluene andwater.

In some embodiments, the solvent comprises a mixture of approximatelyequal parts by weight of toluene and water.

The reacting of a compound of Formula (IV) with a compound of Formula(V) can be carried out at any suitable temperature, readily selected byone skilled in the art.

In some embodiments, the reacting is carried out at a temperature ofabout −10° C. to about 20° C.

In some embodiments, the reacting is carried out at a temperature ofabout −5° C. to about 15° C.

In some embodiments, the reacting is carried out at a temperature ofabout 0° C. to about 15° C.

In some embodiments, the reacting is carried out at a temperature ofabout 5° C. to about 15° C.

Carbamate Formation Step

The present invention further provides processes for preparing compoundsof Formula (IV):

or a salt form thereof; wherein:

R¹ is selected from C₁-C₆ alkyl, aryl and heteroaryl; each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R² is selected from: H, C₁-C₆ alkyl and aryl; wherein said aryl isoptionally substituted with one or two substituents selected from: C₁-C₆alkyl and halogen:

comprising reacting a compound of Formula (VI):

or a salt form thereof; wherein:

R⁷ is a first leaving group;

with a compound of formula (VH):

to form a compound of Formula (IV) or a salt form thereof.

In some embodiments, R¹ is aryl, optionally substituted with one or twosubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is aryl, optionally substituted with F or Cl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R² is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R² is phenyl.

In some embodiments, R⁷ is halogen.

In some embodiments, R⁷ is chlorine.

In some embodiments, R⁷ is heteroaryl.

In some embodiments, R⁷ is benzotriazol-1-yl

In some embodiments, R⁷ is imidazol-1-yl.

In some embodiments, R¹ is 4-chlorophenyl; R² is phenyl; and R⁷ isimidazol-1-yl.

In some embodiments, R¹ is 3-fluorophenyl; R² is phenyl; and R⁷ isimidazol-1-yl.

The reacting of a compound of Formula (VI) with a compound of Formula(VD) can be optionally carried out in the presence of any suitablesolvent, readily selected by one skilled in the art. Example solventsinclude polar to moderately polar solvents or high boiling solvents suchas N,N-dimethylformamide (DMF), N,N-dimethylacetamide, toluene,acetonitrile, propionitrile, tetrahydrofuran and N-methylpyrrolidinone.

In some embodiments, the solvent comprises acetonitrile.

The reacting of a compound of Formula (VI) with a compound of Formula(VD) can be carried out at any suitable temperature, readily selected byone skilled in the art.

In some embodiments, the reacting is carried out at a temperature ofabout 35° C. to about 105° C.

In some embodiments, the reacting is carried out at a temperature ofabout 45° C. to about 95° C.

In some embodiments, the reacting is carried out at a temperature ofabout 55° C. to about 85° C.

In some embodiments, the reacting is carried out at a temperature ofabout 65° C. to about 70° C.

The reacting of a compound of Formula (VI) with a compound of Formula(VII) can be optionally carried out in situ following the reacting of acompound of Formula (VIII) with a compound of Formula (IX) in thepresence of a base to form a compound of Formula (VI), withoutsubstantial purification of the compound of Formula (VI).

Acylation Step

The present invention further provides processes for preparing compoundsof Formula (VI):

or a salt form thereof; wherein:

R¹ is selected from C₁-C₆ alkyl, aryl and heteroaryl; each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen; and

R² is selected from: H, C₁-C₆ alkyl and aryl; wherein said aryl isoptionally substituted with one or two substituents selected from: C₁-C₆alkyl and halogen; and

R⁷ is a first leaving group:

comprising reacting a compound of Formula (VIII):

or a salt form thereof; with a compound of formula (IX):

wherein:

R⁸ is a second leaving group:

to form a compound of Formula (VI) or a salt form thereof.

In some embodiments, R¹ is aryl, optionally substituted with one or twosubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is aryl, optionally substituted with F or Cl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R² is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R² is phenyl.

In some embodiments, R⁷ and R⁸ are both halogen.

In some embodiments, R⁷ and R⁸ are both chlorine.

In some embodiments, R⁷ and R⁸ are both heteroaryl.

In some embodiments, R⁷ and R⁸ are both benzotriazol-1-yl

In some embodiments, R⁷ and R⁸ are both imidazol-1-yl.

In some embodiments, R¹ is 4-chlorophenyl; R² is phenyl; and R¹ and R⁸are both imidazol-1-yl.

In some embodiments, R¹ is 3-fluorophenyl; R² is phenyl; and R⁷ and R⁸are both imidazol-1-yl.

The reacting of a compound of Formula (VI) with a compound of Formula(VII) can be optionally carried out in the presence of any suitablesolvent, readily selected by one skilled in the art. Example solventsinclude polar to moderately polar solvents or high boiling solvents suchas N,N-dimethylformamide (DMF). N,N-dimethylacetamide, toluene,acetonitrile, propionitrile, tetrahydrofuran and N-methylpyrrolidinone.

In some embodiments, the solvent comprises acetonitrile.

The reacting of a compound of Formula (VI) with a compound of Formula(VII) can be carried out at any suitable temperature, readily selectedby one skilled in the art.

In some embodiments, the reacting is carried out at a temperature ofabout 35° C. to about 105° C.

In some embodiments, the reacting is carried out at a temperature ofabout 45° C. to about 95° C.

In some embodiments, the reacting is carried out at a temperature ofabout 55° C. to about 85° C.

In some embodiments, the reacting is carried out at a temperature ofabout 65° C. to about 70° C.

Salt Formation

The present invention further provides processes for preparing salts ofcompounds of Formula

and solvates and hydrates thereof;comprising reacting a compound of Formula (II) with a salt-formingreagent to form a salt of a compound of formula (H).

In some embodiments, R¹ is aryl, optionally substituted with one or twosubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is aryl, optionally substituted with F or Cl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R² is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R² is phenyl.

In some embodiments, R¹ is 4-chlorophenyl and R² is phenyl.

In some embodiments, R¹ is 3-fluorophenyl and R² is phenyl.

In some embodiments, the salt forming reagent is an alkali metalhydroxide.

In some embodiments, the salt forming reagent is sodium hydroxide.

The reacting a compound of Formula (II) with a salt-forming reagent toform a salt of a compound of formula (II) can be optionally carried outin the presence of any suitable solvent, readily selected by one skilledin the art.

In some embodiments, the solvent comprises an alcohol such as ethanol,n-propanol, isopropanol, n-butanol and the like.

In some embodiments, the solvent comprises isopropanol.

In some embodiments, the solvent comprises a mixture of isopropanol andwater.

The reacting a compound of Formula (II) with a salt-forming reagent toform a salt of a compound of formula (H) can be carried out at anysuitable temperature, readily selected by one skilled in the art.

In some embodiments, the reacting is carried out at a temperature ofabout 10° C. to about 70° C.

In some embodiments, the reacting is carried out at a temperature ofabout 20° C. to about 60° C.

In some embodiments, the reacting is carried out at a temperature ofabout 30° C. to about 50° C.

In some embodiments, the reacting is carried out at a temperature ofabout 40° C.

Pharmaceutically Acceptable Salts

Some embodiments of the present invention pertain to pharmaceuticallyacceptable salts of compounds of Formula (II):

In some embodiments, R¹ is aryl, optionally substituted with one or twosubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is aryl, optionally substituted with F or Cl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R² is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R² is phenyl.

In some embodiments, R¹ is 4-chlorophenyl and R² is phenyl.

In some embodiments, R¹ is 3-fluorophenyl and R² is phenyl.

In some embodiments, the pharmaceutically acceptable salt has a purityof 80% or greater.

In some embodiments, the pharmaceutically acceptable salt has a purityof 90% or greater.

In some embodiments, the pharmaceutically acceptable salt has a purityof 95% or greater.

In some embodiments, the pharmaceutically acceptable salt has a purityof 99% or greater.

In some embodiments, the pharmaceutically acceptable salt has a purityof 99.5% or greater.

In some embodiments, the pharmaceutically acceptable salt comprises apharmaceutically acceptable salt of a compound of Formula (II) and acompound of Formula (II) in a ratio of about 4:1 or greater.

In some embodiments, the pharmaceutically acceptable salt comprises apharmaceutically acceptable salt of a compound of Formula (II) and acompound of Formula (II) in a ratio of about 9:1 or greater.

In some embodiments, the pharmaceutically acceptable salt comprises apharmaceutically acceptable salt of a compound of Formula (II) and acompound of Formula (II) in a ratio of about 19:1 or greater.

In some embodiments, the pharmaceutically acceptable salt comprises apharmaceutically acceptable salt of a compound of Formula (II) and acompound of Formula (II) in a ratio of about 99:1 or greater.

In some embodiments, the pharmaceutically acceptable salt is a sodiumsalt.

Intermediates

The present invention further provides intermediates that are useful inthe preparation of compounds of Formula (II) and salts thereof.

Some embodiments pertain to compounds of Formula (III) or a salt formthereof:

In some embodiments, R¹ is aryl, optionally substituted with one or twosubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is aryl, optionally substituted with F or Cl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R² is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R¹ is phenyl.

In some embodiments, R⁵ is tert-butyl.

In some embodiments, R¹ is 4-chlorophenyl; R² is phenyl; and R⁵ istert-butyl.

In some embodiments, R¹ is 3-fluorophenyl; R² is phenyl; and R⁵ istert-butyl.

Some embodiments pertain to compounds of Formula (IV) or a salt formthereof:

In some embodiments, R¹ is aryl, optionally substituted with one or twosubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is aryl, optionally substituted with F or Cl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R² is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R² is phenyl.

In some embodiments, R¹ is 4-chlorophenyl; R² is phenyl.

In some embodiments, R¹ is 3-fluorophenyl; R² is phenyl.

Some embodiments pertain to compounds of Formula (VI) or a salt formthereof:

In some embodiments, R¹ is aryl, optionally substituted with one or twosubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is aryl, optionally substituted with F or Cl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R² is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R² is phenyl.

In some embodiments, R⁷ is halogen.

In some embodiments, R⁷ is chlorine.

In some embodiments, R⁷ is heteroaryl.

In some embodiments, R⁷ is benzotriazol-1-yl In some embodiments, R⁷ isimidazol-1-yl.

In some embodiments, R¹ is 4-chlorophenyl; R² is phenyl; and R⁷ isimidazol-1-yl.

In some embodiments, R¹ is 3-fluorophenyl; R² is phenyl; and R⁷ isimidazol-1-yl.

Pro-Drugs of the Present Invention

The compounds of the Formula (Ia) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the Formula (Ia). Pro-drugs of the present invention mayemploy any pro-drug strategy known in the art. A pro-drug may be used toalter or improve the physical and/or pharmacokinetic profile of theparent compound and can be formed when the parent compound contains asuitable group or substituent which can be derivatized to form apro-drug. Examples of pro-drugs include in-vivo hydrolyzable amides of acompound of the Formula (Ia) or pharmaceutically-acceptable saltsthereof.

One aspect of the present invention pertains to compounds of Formula (X)useful as pro-drugs for the delivery of compounds of Formula (Ia):

wherein:

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein

C₁-C₆ alkyl, aryl and heteroaryl are each optionally substituted withone or two substituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl,C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen;

X is O or NR³;

R³ is selected from: H and C₁-C₆ alkyl; and

R⁹ is a radical derived from any natural or unnatural amino acid, uponthe loss of a hydrogen atom from the α-amino group of said natural orunnatural amino acid; or

R⁹ is —NHCH₂CH₂SO₃H.

One aspect of the present invention pertains to compounds of Formula(Xa) useful as pro-drugs for the delivery of compounds of Formula (Ia):

R¹ and R² are each independently selected from: H, C₁-C₆ alkyl, aryl andheteroaryl; wherein C₁-C₆ alkyl, aryl and heteroaryl are each optionallysubstituted with one or two substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl and halogen;

R¹⁰ is selected from: H and carboxyl; and

R¹¹ is selected from: H and C₁-C₆ alkyl; wherein C₁-C₆ alkyl isoptionally substituted with 4-hydroxyphenyl, amino, carboxamide,carboxyl, guanidino, hydroxyl, imidazolyl, indolyl, methylthio, phenyl,pyrrolidinyl, sulfo and thiol.

In some embodiments, R¹ is aryl, optionally substituted with one or twosubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl and halogen.

In some embodiments, R¹ is aryl, optionally substituted with F or Cl.

In some embodiments, R¹ is 4-chlorophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R² is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆ alkyl and halogen.

In some embodiments, R² is phenyl.

In some embodiments, R¹⁰ is H and R¹¹ is —CH₂SO₃H.

In some embodiments, R¹⁰ is carboxyl and R¹¹ is H.

In some embodiments: R¹ is 4-chlorophenyl; R² is phenyl; R¹⁰ is H andR¹¹ is —CH₂SO₃H.

In some embodiments: R¹ is 4-chlorophenyl; R² is phenyl; R¹⁰ is carboxyland R¹¹ is H.

In some embodiments: R¹ is 3-fluorophenyl; R¹ is phenyl; R¹⁰ is H andR¹¹ is —CH₂SO₃H.

In some embodiments: R¹ is 3-fluorophenyl; R¹ is phenyl; R¹⁰ is carboxyland R¹¹ is H.

Certain pro-drugs of compounds of the present invention are described inExamples 1.112, 1.113 and 9-11.

Other Utilities

Another object of the present invention relates to radio-labeledcompounds of the present invention that would be useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating the PGI2 receptor in tissue samples,including human and for identifying PGI2 receptor ligands by inhibitionbinding of a radio-labeled compound. It is a further object of thisinvention to develop novel PGI2 receptor assays of which comprise suchradio-labeled compounds.

The present invention embraces isotopically-labeled compounds of thepresent invention. Isotopically or radio-labeled compounds are thosewhich are identical to compounds disclosed herein, but for the fact thatone or more atoms are replaced or substituted by an atom having anatomic mass or mass number different from the atomic mass or mass numbermost commonly found in nature. Suitable radionuclides that may beincorporated in compounds of the present invention include but are notlimited to ²H (also written as D for deuterium), ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound. For example,for in vitro PGI2 receptor labeling and competition assays, compoundsthat incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I or ³³S will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound of Formula (Ia), (Ic), (Ie), (Ig), (Ii), (Ik), (Im) or (II)that has incorporated at least one radionuclide; in some embodiments theradionuclide is selected from the group consisting of ³H, ¹⁴C, ¹²³I, ³⁵Sand ⁸²Br.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Drawings and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the scarcer radio-isotope or nonradioactiveisotope. Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas: This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]: This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters and the like.

C. Reduction with Lithium Aluminum Hydride [³H]: This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters and the like.

D. Tritium Gas Exposure Labeling: This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]: This procedure is usuallyemployed to prepare O-methyl or N-methyl (³H) products by treatingappropriate precursors with high specific activity methyl iodide (³H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions: This procedure transforms an aryl amineor a heteroaryl amine into a diazonium salt, such as a diazoniumtetrafluoroborate salt and subsequently to ¹²⁵I labeled compound usingNa¹²⁵I. A represented procedure was reported by Zhu, G-D. and co-workersin J. Org. Chem., 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols: This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labelled Compd. Radiopharm., 1999,42, S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I: This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkytin intermediateusing for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)₄] or throughan aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalideor hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃].

A representative procedure was reported by Le Bas, M.-D. and co-workersin J. Labelled Compd. Radiopharm. 2001, 44, S280-S282.

A radiolabeled PGI2 receptor compound of Formula (Ia) can be used in ascreening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radio-labeledcompound of Formula (In)” to the PGI2 receptor. Accordingly, the abilityof a test compound to compete with the “radio-labeled compound ofFormula (Ia)” for the binding to the PGI2 receptor directly correlatesto its binding affinity.

The labeled compounds of the present invention bind to the PGI2receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labeled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 μM and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those skilled in the art based upon, inter alia, a review of thisdisclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1: Syntheses of Compounds of the Present Invention

Illustrated syntheses for compounds of the present invention are shownin FIGS. 1 through 6 where the symbols have the same definitions as usedthroughout this disclosure.

The compounds of the invention and their syntheses are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulars of these examples. The compounds describedherein, supra and infra, are named according to the CS ChemDraw UltraVersion 7.0.1, AutoNom version 2.2, or CS ChemDraw Ultra Version 9.0.7.In certain instances common names are used and it is understood thatthese common names would be recognized by those skilled in the art.

Chemistry: Proton nuclear magnetic resonance (¹H NMR) spectra wererecorded on a Bruker Avance-400 equipped with a QNP (Quad Nucleus Probe)or a BBI (Broad Band Inverse) and z-gradient. Chemical shifts are givenin parts per million (ppm) with the residual solvent signal used asreference. NMR abbreviations are used as follows: s=singlet, d=doublet,dd=doublet of doublets, ddd=doublet of doublet of doublets, dt=doubletof triplets, t=triplet, td=triplet of doublets, tt=triplet of triplets,q=quartet, m=multiplet, bs=broad singlet, bt=broad triplet. Microwaveirradiations were carried out using a Smith Synthesizer™ or an EmrysOptimizer™ (Biotage). Thin-layer chromatography (TLC) was performed onsilica gel 60 F254 (Merck), preparatory thin-layer chromatography (prepTLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman) andcolumn chromatography was carried out on a silica gel column usingKieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done under reducedpressure on a Buchi rotary evaporator.

LCMS spec: HPLC-pumps: LC-LOAD VP, Shimadzu Inc. HPLC system controller:SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, Shimadzu Inc;Autosampler. CTC I-ITS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.

Example 1.1: Preparation of tert-Butyl2-(((1s,4s)-4-((Phenykarbamoyloxy)methyl)cyclohexyl)methoxy)acetate StepA: Preparation of (1s,4s)-Diethyl Cyclohexane-1,4-dicarboxylate

To a solution of (1 s,4s)-cyclohexane-1,4-dicarboxylic acid (25 g, 145mmol) in ethanol (150 mL) was added concentrated H₂SO₄ (98%, 1 mL). Thereaction was heated to reflux for 16 h, cooled to room temperature andconcentrated. The residue was extracted with EtOAc and saturated NaHCO₃,washed with brine, dried over MgSO₄, and filtered. The filtrate wasconcentrated to provide the title compound as colorless oil (30.5 g). ¹HNMR (400 MHz, CDCl₃) δ ppm 1.25 (t, J=7.14 Hz, 6H), 1.62-1.75 (m, 4H),1.84-1.97 (m, 4H), 2.40-2.50 (m, 2H), 4.13 (q, J=7.12 Hz, 4H).

Step B: Preparation of (1s,4s)-Cyclohexane-1,4-diyldimethanol

To a solution of (1s,4s)-diethyl cyclohexane-1,4-dicarboxylate (13.0 g,56.9 mmol) in THE (500 mL) was added lithium aluminum hydride (4.54 g,120 mmol) in portions at 0° C. The mixture was stirred at thattemperature for 2 h and quenched with cold water, filtered andconcentrated to give the title compound as colorless oil (8.2 g). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.25-1.44 (m, 8H), 1.45-1.56 (m, 2H), 3.24-3.33(m, 4H), 4.29 (t, J=5.31 Hz, 2H).

Step C: Preparation of ((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methylPhenylcarbamate

To a solution of (1s,4s)-cyclohexane-1,4-diyldimethanol (3.0 g, 20.80mmol) in pyridine (100 mL) were added phenyl isocyanate (2.478 g, 20.80mmol). The reaction was stirred overnight at room temperature. Themixture was concentrated and purified via silica gel columnchromatography to provide the title compound as colorless oil (2.55 g).LCMS m/z=264.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37-1.61 (m, 8H),1.63-1.76 (m, 1H), 1.85-1.97 (m, 1H), 3.54 (d, J=6.95 Hz, 2H), 4.10 (d,J=7.20 Hz, 2H), 6.72 (s, 1H), 7.02-7.08 (m, 1H), 7.25-7.33 (m, 2H),7.34-7.41 (m, 2H).

Step D: Preparation of tert-Butyl2-(((1s,4s)-4-((Phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate

To a solution of ((1s,4s)-4-(hydroxymethyl)cyclohexyl)methylphenylcarbamate (1.55 g, 5.89 mmol) in CH₂Cl₂ (100 mL) was addeddiacetoxyrhodium (0.15 g, 0.339 mmol) and tert-butyl 2-diazoacetate(0.837 g, 5.89 mmol) and the mixture was stirred for 2 h at 0° C. Themixture was concentrated and purified via silica gel columnchromatography to provide the title compound as colorless oil (1.85 g).LCMS m/z=378.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.40-1.64 (m, 8H),1.48 (s, 9H), 1.79-1.95 (m, 2H), 3.42 (d, J=6.95 Hz, 2H), 3.94 (s, 2H),4.09 (d, J=7.20 Hz, 2H), 6.63 (s, 1H), 7.02-7.08 (m, 1H), 7.25-7.33 (m,2H), 7.35-7.41 (m, 2H).

Example 1.2: Preparation of2-(((1s,4s)-4-(((4-Methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 24)

To a solution of tert-butyl 2-(((1s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate (0.1 g,0.265 mmol) in dioxane (2 mL) were added 1-iodo-4-methoxybenzene (0.062g, 0.265 mmol), (1R,2R)-cyclohexane-1,2-diamine (0.030 g, 0.265 mmol),CuI (0.02 g, 0.158 mmol), and K₃PO₄ (0.1 g, 0.471 mmol) at roomtemperature. The reaction mixture was sealed in a reaction vial andheated to 150° C. under microwave irradiation for 4 h. The mixture wasfiltered and the filtrate was concentrated. The residue was treated withHCl (4.0 N in dioxane, 5 mL) for 16 h. The resulting mixture wasconcentrated and purified by preparative HPLC. LCMS m/z=428.2 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.56 (m, 8H), 1.70-1.88 (m, 2H), 3.31(s, 3H), 3.39 (d, J=7.07 Hz, 2H), 4.00 (d, J=7.20 Hz, 2H), 4.11 (s, 2H),6.94-7.01 (m, 2H), 7.23-7.31 (m, 4H), 7.42-7.49 (m, 3H).

Example 1.3: Preparation of2-(((1s,4s)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 25)

From tert-butyl2-(((1s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-chloro-4-iodobenzene, using a similar method to the one described inExample 1.2, the title compound was obtained. LCMS m/z=432.1 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.53 (m, 8H), 1.60-1.81 (m, 2H), 3.29(d, J=7.07 Hz, 2H), 3.96 (s, 2H), 3.98 (d, J=6.69 Hz, 2H), 7.24-7.33 (m,5H), 7.36-7.48 (m, 4H).

Example 1.4: Preparation of2-(((1s,4s)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 26)

From tert-butyl2-(((1s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohex)methoxy)acetate and1-fluoro-3-iodobenzene, using a similar method to the one described inExample 1.2, the title compound was obtained. LCMS m/z=416.4 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.42 (m, 8H), 1.71 (s, 2H), 3.28 (d,J=7.07 Hz, 2H), 3.% (s, 2H), 3.99 (d, J=6.44 Hz, 2H), 7.03-7.11 (m, 2H),7.20-7.33 (m, 4H), 7.37-7.43 (m, 3H).

Example 1.5: Preparation of2-(((1s,4s)-4-(((3-Chlorophenyl)(phenyl)carbamoyloxyknethyl)cyclohexyl)methoxy)aceticAcid (Compound 30)

From tert-butyl2-(((1s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-chloro-3-iodobenzene, using a similar method to the one described inExample 1.2, the title compound was obtained. LCMS m/z=432.1 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.27-1.55 (m, 8H), 1.60-1.87 (m, 2H), 3.29(d, J=7.07 Hz, 2H), 3.96 (s, 2H), 399 (d, J=6.57 Hz, 2H), 7.18-7.34 (m,5H), 7.35-7.48 (m, 4H).

Example 1.6: Preparation of2-(((1s,4s)-4-((Phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 31)

From tert-butyl2-(((1s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-iodo-3-methylbenzene, using a similar method to the one described inExample 1.2, the title compound was obtained. LCMS m/z=412.2 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.53 (m, 8H), 1.60-1.76 (m, 2H), 2.27(s, 3H), 3.28 (d, J=6.95 Hz, 2H), 3.95 (s, 2H), 4.00 (d, J=7.20 Hz, 2H),7.02-7.11 (m, 3H), 7.19-7.29 (m, 4H), 7.33-7.39 (m, 2H).

Example 1.7: Preparation of2-(((1s,4s)-4-(((2-Methoxyphenylxphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 32)

From tert-butyl2-(((1s,4s)-4-(phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1 iodo-2-methoxybenzene, using a similar method to the one described inExample 1.2, the title compound was obtained. LCMS m/z=428.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.56 (m, 8H), 1.70-1.88 (m, 2H), 3.32(s, 3H), 3.40 (d, J=7.07 Hz; 2H), 4.00 (d, J=7.33 Hz, 2H), 4.11 (s, 2H),6.93-7.02 (m, 2H), 7.23-7.31 (m, 4H), 7.42-7.49 (m, 3H).

Example 1.8: Preparation of2-(((1s,4s)-4-(((3-MethoxyphenylXphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 33)

From tert-butyl2-(((1s,4s)-4-(phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-iodo-3-methoxybenzene, using a similar method to the one described inExample 1.2, the title compound was obtained. LCMS m/z=428.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.56 (m, 8H), 1.71-1.88 (m, 2H), 3.32(s, 3H), 3.40 (d, J=7.07 Hz, 2H), 4.00 (d, J=7.33 Hz, 2H), 4.11 (s, 2H),6.94-7.01 (m, 2H), 7.23-7.30 (m, 4H), 7.43-7.48 (m, 3H).

Example 1.9: Preparation of2-(((1s,4s)-4-((Phenyl(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 34)

From tert-butyl2-(((1s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-iodo-4-methylbenzene, using a similar method to the one described inExample 1.2, the title compound was obtained. LCMS m/z=412.2 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.53 (m, 8H), 1.59-1.80 (m, 2H), 2.29(s, 3H), 3.38 (d, J=7.07 Hz, 2H), 3.96 (s, 2H), 4.00 (d, J=7.20 Hz, 2H),7.13-7.21 (m, 2H), 7.21-7.30 (m, 4H), 7.32-7.39 (m, 3H).

Example 1.10: Preparation of2-(((1s,4s)-4-(((4-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 35)

From tert-butyl2-(((1s,4s)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-fluoro-4-iodobenzene, using a similar method to the one described inExample 1.2, the title compound was obtained. LCMS m/z=416.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.54 (m, 8H), 1.60-1.75 (m, 2H), 3.29(d, J=7.07 Hz, 2H), 3.96 (S, 2H), 3.97 (d, J=6.69 Hz, 2H), 7.17-7.31 (m,5H), 7.31-7.41 (m, 4H).

Example 1.11: Preparation of2-(((1s,4s)-4-((Diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 7) Step A: Preparation of((1s,4c)-4-(Hydroxymethyl)cyclohexyl)methyl diphenylcarbamate

To a solution of (1s,4s)-cyclohexane-1,4-diyldimethanol (0.560 g, 3.88mmol) in pyridine (5 mL) was added diphenylcarbamic chloride (0.9 g,3.88 mmol) at room temperature. The reaction was refluxed for 5 h,cooled to room temperature, and concentrated under reduced pressure. Theresidue was poured into water. The organic material was extracted withethyl acetate and washed with 1.0 M HCl. The extract was dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography to provide the title compound (0.870g). LCMS m/z=340.23 [M+H]⁺.

Step B: Preparation of2-(((1s,4s)-4-((Diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of ((1 s,4s)-4-(hydroxymethyl)cyclohexyl)methyldiphenylcarbamate (300 mg, 0.884 mmol) and diacetoxyrhodium (19.53 mg,0.044 mmol) in CH₂Cl₂ (3 mL), was added dropwise a solution of ten-butyl2-diazoacetate (188 mg, 1.326 mmol) in CH₂Cl₂ (1 mL) at 0° C. Afterstirring for 1 h at room temperature, the reaction was filtered andconcentrated under reduced pressure. The residue was treated with HCl(4.0 M in dioxane, 2 mL). After stirring for 8 h, the reaction wasconcentrated under reduced pressure and the residue was purified by HPLCto provide the title compound (198 mg). LCMS m/z=398.45 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 1.15-1.40 (m, 8H), 1.50-1.62 (m, 2H), 1.75-1.81 (m,2H), 3.90-3.92 (d, J=4.3 Hz, 2H), 3.96 (s, 2H), 7.21-7.32 (m, 6H),7.35-7.39 (m, 4H).

Example 1.12: Preparation of Sodium2-(((1r,4r)-4-((Diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate

To a solution of2-(((1r,4r)-4-((diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy) aceticacid (25 mg, 0.063 mmol) in MeOH (1 mL), was added sodium methanolate(0.126 mL, 0.063 mmol) at −10° C. After stirring for 30 min, thereaction was concentrated under reduced pressure to provide the titlecompound as a white solid (26.1 mg). LCMS m/z=398.41 [M+H]⁺.

Example 1.13: Preparation of2-(((1r,4r)-4-(((3-Methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 14) Step A: Preparation of((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl Phenylcarbamate

To a solution of (1r,4r)-cyclohexane-1,4-diyldimethanol (5 g, 34.7 mmol)in pyridine, was added phenyl isocyanate (4.13 g, 34.7 mmol) at roomtemperature. The reaction was stirred for 5 h, concentrated andextracted with ethyl acetate. The extract was dried over MgSO₄ andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (4.69 g). LCMS m/z: =2 (443[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-1.09 (m, 4H), 1.30-1.39 (m,1H), 1.51-1.62 (m, 1H), 1.75-1.88 (m, 4H), 3.15-3.25 (d, J=5.8 Hz, 2H),3.82-3.95 (d, J=6.56 Hz, 2H), 4.52 (t, J=5.31 Hz, 1H), 6.29 (m, 1H),7.30 (m, 2H), 7.48 (m, 2H), 9.62 (s, 1H).

Step B: Preparation of ten-Butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl) cyclohexyl)methoxy) Acetate

To a solution of ((1r,4r)-4-(hydroxymethyl)cyclohexyl)methylphenylcarbamate (2.5 g, 9.49 mmol) and diacetoxyrhodium (0.210 g, 0.475mmol) in dichloromethane (50 mL) was added dropwise a solution oftert-butyl 2-diazoacetate (1.350 g, 9.49 mmol) in dichloromethane (5 mL)at 0° C. for 20 min. After stirring for 30 min at room temperature, thesolid was filtered off and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound (3.32 g). LCMS m/z=378.43 [M+H]⁺; ¹H NMR (400MHz; DMSO-d₆) δ ppm 0.85-1.08 (m, 4H), 1.42 (s, 9H), 1.41-1.62 (m, 2H),1.78-1.81 (m, 4H), 3.25 (d, J=6.3 Hz, 2H), 3.92 (d, J=4.6 Hz; 2H), 6.29(m, 1H), 7.31 (m, 2H), 7.48 (m, 2H), 9.62 (s, 1H).

Step C: Preparation of 2-(((1r,4r)-4(((3-Methoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic Acid

To a solution of tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy) acetate(0.2 g, 0.530 mmol) in dioxane (95 mL) were added1-bromo-3-methoxybenzene (0.099 g, 0.530 mmol),(1R,2R)-cyclohexane-1,2-diamine (0.012 g, 0.106 mmol), copper(I) iodide(10.09 mg, 0.053 mmol), and K₃PO₄ (0.225 g, 1.060 mmol) at roomtemperature. The reaction was irradiated under microwave for 4 h at 150°C. The reaction mixture was filtered and concentrated under reducedpressure. The residue was treated with HCl (4.0 M in dioxane, 5 mL).After stirring for 10 h, the reaction was concentrated under reducedpressure and the residue was purified by preparative HPLC to provide thetitle compound (0.123 g). LCMS m/z=428.52 [M+H]⁺; ¹H NMR (400 MHz.DMSO-d₆) δ ppm 0.85-1.90 (m, 4H), 1.35-1.50 (s, 2H), 1.51-1.72 (m, 4H),3.25 (d, J=6.4 Hz; 2H), 3.72 (s, 3H), 3.92 (d, J=6.1 Hz, 2H), 6.81-6.89(m, 3H), 7.21-7.45 (m, 6H).

Example 1.14: Preparation of2-(((1r,4r)-4-((1-Methyl-3,3-diphenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 4) Step A: Preparation of1-(((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl)-1-methyl-3,3-diphenylurea

To a solution of ((1r,4r)-4-((methylamino)methyl)cyclohexyl)methanol(0.339 g, 2.158 mmol) in pyridine (3 mL) was added diphenylcarbamicchloride (0.5 g, 2.158 mmol) at room temperature. The reaction wasrefluxed for 5 h. The mixture was cooled to room temperature and pouredinto water. The organic material was extracted and washed with 10 M HCl.The extract was dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto provide the title compound (0.685 g). LCMS m/z=353.16 [M+H]⁺.

Step B: Preparation of2-(((1r,4r)-4-((1-Methyl-3,3-diphenylureido)methyl)cyclohexyl)methoxy)aceticAcid

To a solution of1-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)-1-methyl-3,3-diphenylurea(0.1 g, 0.284 mmol) in CH₂Cl₂ (5 mL), was added rhodium (H) acetatedimer (6.27 mg, 0.014 mmol) followed by tert-butyl 2-diazoacetate (0.040g, 0.284 mmol) at 0° C. The reaction was stirred for 1 h andconcentrated under reduced pressure. The residue was treated with 4.0 MHCl in dioxane and stirred overnight. The mixture was concentrated underreduced pressure and the residue was purified by preparative HPLC toprovide the title compound (58 mg). LCMS m/z=411.32 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.35-1.41 (m, 2H), 1.81-1.92 (m, 1H), 2.21-2.51 (m,4H), 2.62-2.86 (m, 2H), 3.21 (m, 2H), 4.62 (s, 3H), 7.15-7.38 (m, 10H).

Example 1.15: Preparation of2-(((1r,4r)-4-((Diphenylcarbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 5)

From (1r,4r)-cyclohexane-1,4-diyldimethanol, the title compound wasobtained using a similar method to the one described in Example 1.11.LCMS m z=398.10 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.10-1.42 (m, 8H),1.53-1.60 (m, 2H), 1.70-1.87 (m, 2H), 3.91-3.93 (d, J=4.2 Hz, 2H), 3.98(s, 2H), 7.20-7.31 (m, 6H), 7.30-7.50 (m, 4H).

Example 1.16: Preparation of2-(((1s,4s)-4-((3,3-Diphenylureido)methyl)cyclohexyl)methoxy)acetic Acid(Compound 9) Step A: Preparation of(1s,4s)-Cyclohexane-1,4-diyldimethanol

To a mixture of (1 s,4s)-cyclohexane-1,4-dicarboxylic acid (4 g, 23.23mmol) in THE (30 mL) was added lithium aluminum hydride (1 M, 93 mL, 93mmol) dropwise at 0° C. The mixture was stirred at room temperatureovernight. The reaction was quenched with water, extracted with EtOAc(3×40 mL), and dried over anhydrous MgSO₄. The mixture was filtered andthe filtrate was concentrated under reduced pressure to provide thetitle compound as colorless oil (3.3 g). ¹H NMR (400 MHz; CDCl₃) δ ppm1.6-1.38 (m, 8H), 1.70 (m, 2H), 3.56 (d, J=4 Hz, 4H).

Step B: Preparation of tert-Butyl2-(((1s,4s)-4-(Hydroxymethyl)cyclohexyl)methoxy)acetate

To a mixture of (1 s,4s)-cyclohexane-1,4-diyldimethanol (1.0 g, 6.93mmd) and rhodium(11) acetate dimer (0.184 g, 0.416 mmol) in DCM (10 mL)was added tert-butyl 2-diazoacetate (1.281 g, 9.01 mmol) dropwise atroom temperature over 1 h period. The mixture was stirred overnight. Themixture was purified via column chromatography to provide the titlecompound as pale yellow oil (0.89 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.42(m, 4H), 1.48 (s, 9H), 1.54 (m, 4H), 1.68 (m, 1H), 1.86 (m, 1H), 3.43(d, 2H, J=8 Hz), 3.55 (d, 2H, J=8 Hz), 3.94 (s, 2H).

Step C: Preparation of tert-Butyl2-(((1s,4s)-4-((Methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate

To a mixture of tert-butyl2-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (0.87 g, 3.37mmol) and triethylamine (1.408 mL, 10.10 mmol) in DCM (10 mL) was addedmethanesulfonyl chloride (0.579 g, 5.05 mmol) at 0° C. The mixture wasstirred at 0° C. for 5 h. The reaction was quenched with water andextracted with DCM (3×20 mL) and dried over anhydrous MgSO₄. The mixturewas filtered and concentrated under reduced pressure to provide thetitle compound as pale yellow oil (1.1 g).

Step D: Preparation of tat-Butyl2-(((1s,4s)-4-(Aminomethyl)cyclohexyl)methoxy) acetate

A mixture of tert-butyl2-(((1s,4s)-4-((methylsulfonyloxy)methyl)cyclohexyl)methoxy)acetate(0.25 g, 0.743 mmol) and sodium azide (0.097 g, 1.486 mmol) in DMF (5mL) was stirred for 48 h. The reaction was diluted with EtOAc (20 mL)and washed with water. The organic layer was dried over anhydrous MgSO₄and concentrated under reduced pressure. The residue was dissolved intoMeOH (5.00 mL) and added Pd/C (3.95 mg, 0.037 mmol). The mixture wasstirred under H2 atmosphere overnight. The mixture was filtered througha celite column and concentrated under reduced pressure to provide thetitle compound as yellow oil (0.164 g) without further purification.LCMS m/z=258.2 [M+H]⁺.

Step E: Preparation of2-(((1s,4s)-4-((3,3-Diphenylureido)methyl)cyclohexyl)methoxy)acetic Acid

To a mixture of tert-butyl2-(((1s,4s)-4-(aminomethyl)cyclohexyl)methoxy)acetate (50 mg, 0.194mmol) in THF (5 mL) was added potassium tert-butoxide (65.4 mg, 0.583mmol) at room temperature. After stirring for 10 min, diphenylcarbamicchloride (45.0 mg, 0.194 mmol) was added. The reaction mixture wasstirred at room temperature overnight. The reaction was quenched withwater and the mixture was purified by preparative HPLC to provide thetitle compound as a white solid (6 mg). LCMS m/z=397.2 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 0.93 (m, 4H), 1.44 (m, 1H), 1.58 (m, 1H), 1.74(d, J=11 Hz, 2H), 1.83 (d, J=11 Hz, 2H), 3.10 (t, J=6.3 Hz, 2H), 3.38(d, J×6.3 Hz, 2H), 4.06 (s, 2H), 4.59 (t, J=5.8 Hz, 1H), 7.21 (dd,J₁=J₂=7.2 Hz, 2H), 7.26 (m, 4H), 7.35 (m, 4H).

Example 1.17: Preparation of2-(((1r,4r)-4-((3-Benzhydryl-3-methylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 48)

A solution of N-methyl-1, 1-diphenylmethanimine (25 mg, 0.127 mmol),triphosgene (41.4 mg, 0.139 mmol), triethylamine (0.088 mL, 0.634 mmol)in DCM (5 mL) was refluxed at 40° C. for 3 h. tert-Butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate (48.9 mg, 0.190mmol) was added. The reaction mixture was refluxed overnight, quenchedwith H₂O, and extracted with DCM. The organic layer was washed withbrine, dried over MgSO₄ and concentrated. The residue was purified bypreparative LCMS to provide the title compound as a white solid (7.6mg). LCMS m/z=425.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.82-1.02 (m,4H), 1.41 (m, 1H), 1.57 (m, 1H), 1.70 (d, J=10.36 Hz, 2H), 1.80 (d,J=10.36 Hz, 2H), 2.72 (s, 3H), 3.11 (t, J=5.68 Hz, 2H), 3.36 (d, J=6.32Hz, 2H), 4.06 (s, 2H), 4.53 (m, 1H), 6.64 (s, 1H), 7.19 (d, J=7.07 Hz,4H), 7.27-7.38 (m, 6H).

Example 1.18: Preparation of2-(((1r,4r)-4-(((2,3-Difluorophenylxphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 51) Step A: Preparation of 2,3-Difluoro-N-phenylaniline

A mixture of 1-bromo-2,3-difluorobenzene (0.232 mL, 2.073 mmd), aniline(0.208 mL, 2.280 mmol), Pd₂(dba)₃ (95 mg, 0.104 mmd), BINAP (194 mg,0.311 mmol), sodium tert-butoxide (299 mg, 3.11 mmol), and toluene (3mL) in a sealed vessel under argon was heated in an oil bath at 110° C.overnight. The reaction mixture was filtered through a plug of celite.The filtrate was concentrated and the residue was purified by silica gelcolumn chromatography to give the title compound as a light brown oil(411 mg). LCMS m/z=206.1 [M+H]⁺; ¹H NMR (400 MHz, Methanol-d₆) δ ppm6.53-6.644 (m, 1H), 6.80-6.88 (m, 2H), 6.88-6.95 (m, 1H), 6.95-7.03 (m,2H), 7.11-7.19 (m, 2H).

Step B: Preparation of 2,3-Difluorophenyl(phenyl)carbamic Chloride

2,3-Difluoro-N-phenylaniline (100 mg, 0.487 mmd) and triphosgene (159mg, 0.536 mmol) were dissolved in CH₂Cl₂ (1 mL). The solution was cooledin an ice bath, and pyridine (79 μL, 0.975 mmol) was added slowly. Uponcomplete addition, the reaction was warmed to room temperature andstirred for 1 h. Then, it was cooled in an ice bath and quenched by theslow addition of H₂O (1 mL). The reaction mixture was extracted with H₂O(5 mL) and CH₂Cl₂ (5 mL). The aqueous layer was extracted again withCH₂Cl₂ (5 mL). The organic layers were combined and washed once with H₃O(10 mL), dried over MgSO₄, and concentrated. The residue was purified bysilica gel column chromatography to yield the title compound as a lightbrown oil (114.7 mg).

Step C: Preparation of2-(((1r,4r)-4-(((2,3-Difluorophenylxphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid

2,3-Difluorophenyl(phenyl)carbamic chloride (50 mg, 0.187 mmol) andtert-butyl 2-(((1r,4r)-4-(hydroxymethyl) cyclohexyl)methoxy)acetate(48.3 mg, 0.187 mmd) were dissolved in pyridine (1 mL). The reactionmixture was heated to 100° C. and stirred overnight. The solvent wasremoved from the mixture and the residue was purified by silica gelcolumn chromatography to provide an oil, which was redissolved in HCl (4M in dioxane) (500 μL, 1.999 mmol). The reaction mixture was stirred atroom temperature for 5 h. After removal of the solvent, the residue waspurified by preparative LCMS to provide the title compound as a whitesolid (12.3 mg). LCMS m/z=434.2 [M+H]⁺; ¹H NMR (400 MHz, Methanol-d₆) δppm 0.78-0.94 (m, 4H), 1.32-1.49 (m, 2H), 1.51-1.62 (m, 2H), 1.63-1.77(m, J=7.33 Hz, 2H), 3.20-3.22 (m, 2H), 3.89 (d, J=6.0 Hz, 2H), 3.92 (s,2H), 6.99-7.10 (m, 2H), 7.11-7.22 (m, 4H), 7.22-7.31 (m, 2H).

Example 1.19: Preparation of Sodium2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateStep A: Preparation of 4-Chlorophenyl(phenyl)carbamic Chloride

From 4-chloro-N-phenylaniline, using a similar method to the onedescribed in Example 1.18, Step B, the title compound was obtained as alight yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.31-7.81 (m, 9H).

Step B: Preparation of ((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl4-chlorophenyl(phenyl)carbamate

4-Chlorophenyl(phenyl)carbamic chloride (12.34 g, 46.4 mmd) and(1r,4r)-cyclohexane-1,4-diyldimethanol (6.69 g, 46.4 mmol) weredissolved in pyridine (50 mL, 618 mmol). The reaction mixture was heatedto reflux overnight, cooled and concentrated under reduced pressure. Theresidue was resuspended in Et₂O/EtOAc (50:50), filtered and washed withEtOAc and Et₂O. The filtrate was extracted with 1 M HCl (200 mL) andEtOAc (200 mL). The aqueous layer was extracted again with EtOAc (100mL). The organic layers were combined and washed with H₂O (200 mL),dried, and concentrated. The residue was purified by silica gel columnchromatography to provide the title compound as a light pink coloredsolid (10.4 g). LCMS m/z=374.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.73-0.92 (m, 4H), 1.13-1.27 (m, 1H), 1.36-1.50 (m, 1H), 1.53-1.62 (m,2H), 1.62-1.73 (m, 2H), 3.17 (d, J=6.19 Hz, 2H), 3.89 (d, J=6.06 Hz,2H), 4.29 (bs, 1H), 7.23-7.32 (m, 5H), 7.34-7.45 (m, 4H).

Step C: Preparation of tert-Butyl2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexylmethoxy)acetate

((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl4-chlorophenyl(phenyl)carbamate (8.9 g, 23.80 mmol) was dissolved inCH₂Cl₂ (30 mL). Diacetoxyrhodium (0.526 g, 1.190 mmol) was added and thereaction was cooled on an ice bath, test-Butyl 2-diazoacetate (3.63 mL,26.2 mmol) pre-dissolved in CH₄Cl₂ (10 mL) was added slowly to thereaction via an addition funnel. The reaction was stirred in an ice bathfor 1 h, warmed to room temperature and stirred for an additional 1 h.After removal of the solvent, the residue was purified by silica gelcolumn chromatography to provide the title compound as a colorless oil(8.8 g). LCMS m/z=432.6 [M-tert-butyl group+H]⁺, ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.77-0.95 (m, 4H), 1.33-1.50 (m, 2H), 1.42 (s, 9H),1.52-1.62 (m, 2H), 1.63-1.75 (m, 2H), 3.22 (d, J=6.32 Hz, 2H), 3.83-3.93(m, 4H), 7.23-7.32 (m, 5H), 7.35-7.44 (m, 4H).

Step D: Preparation of Sodium2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate

tert-Butyl 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate (8.8 g, 18.03 mmol) was dissolved in HCl (4 Min dioxane, 100 mL, 400 mmol). The reaction was stirred at roomtemperature overnight and concentrated under reduced pressure to providean oil. The oil was extracted with H2O (100 mL) and EtOAc (100 mL). Theaqueous layer was extracted again with EtOAc (100 mL). The combinedorganic layer was washed with H2O (150 mL), dried, and concentrated toyield a light yellow oil. The oil was dissolved in a minimal amount ofMeOH (10-20 mL) and cooled in an ice bath. NaOH (1 M, 27.0 mL, 27.0mmol) was added with stirring. A white solid precipitate was formed. Themixture was diluted with H₂O (20 mL). The solid was filtered and washedwith cold H₂O (20 mL). The solid was dried in a vacuum oven (60° C.overnight) to provide the title compound as a white solid (7.7 g).LCMS=432.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73-0.93 (m, 4H),128-1.40 (bs, 1H), 1.40-1.50 (bs, 1H), 1.50-1.61 (m, 2H), 1.63-1.77 (m,2H), 3.16 (d, J=6.57 Hz, 2H), 3.47 (s, 2H), 3.89 (d, J=6.06 Hz, 2H),7.23-7.32 (m, 5H), 7.35-7.44 (m, 4H).

Example 1.20: Preparation of Sodium2-(((1r,4r)-4-(((4-Fluorophenyl)(phenyl)carbamoyloxy)methg)cyclohexyl)methoxy)acetate

From 4-fluoro-N-phenylaniline, using a similar method to the onedescribed in Example 1.19, the title compound was obtained as a whitesolid. LCMS m/z=416.4 [M+H]⁺; ¹H NMR (400 MHz; DMSO-d₆) δ ppm 0.72-0.94(m, 4H), 1.28-1.39 (m, 1H), 1.39-1.49 (m, 1H), 1.50-1.61 (m, 2H),1.62-1.76 (m, 2H), 3.15 (d, J=6.44 Hz, 2H), 3.45 (s, 2H), 3.88 (d,J=6.06 Hz, 2H), 7.16-7.41 (m, 9H).

Example 1.21: Preparation of2-(((1r,4r)-4-(((4-Methoxyphenyl)(phenyl)carbamoyloxy)methyll)cyclohexyl)methoxy)aceticAcid (Compound 21)

tert-Butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate(50.0 mg, 0.132 mmol), copper(I) iodide (12.61 mg, 0.066 mmol), K₃PO₄ e(56.2 mg, 0.265 mmol), 4-methoxyphenyl iodide (31.0 mg, 0.132 mmol) anddioxane (1.6 mL) were added to a vial. The reaction was heated undermicrowave irradiation at 150° C. for 4-5 h. The reaction mixture wasfiltered through a plug of MgSO₄. The solvent was evaporated and theresulting oil was redissolved in HCl (4 M in dioxane, 497 μL, 1.987mmol). The mixture was stirred overnight. After removal of the solvent,the residue was purified by preparative LCMS to provide the titlecompound as a white solid (12.2 mg). LCMS m/z=428.4 [M+H]⁺.

Example 1.22: Preparation of2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxyknethyl)cyclohexyl)methoxy)aceticAcid (Compound 22)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-chloro-4-iodobenzene, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=432.5 [M+H]⁺.

Example 1.23: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 23)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-fluoro-3-iodobenzene, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=416.5 [M+H]⁺.

Example 1.24: Preparation of2-(((1r,4r)-4-((Phenyl(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 27)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-iodo-3-methylbenzene, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=412.2 [M+H]⁺.

Example 1.25: Preparation of2-(((1r,4r)-4-(((3-Chlorophenyl)(phenyl)carbamoyloxyknethyl)cyclohexyl)methoxy)aceticAcid (Compound 28)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-chloro-3-iodobenzene, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=432.6 [M+H]⁺.

Example 1.26: Preparation of2-(((1r,4r)-4-(((4-Chloro-3-fluorophenyl)(phenyl)carbamoyloxy)methypcyclohexyl)methoxy)aceticAcid (Compound 36)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-chloro-2-fluoro-4-iodobenzene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=450.1 [M+H]⁺; ¹H NMR (400 MHz; Methanol-d₆) δ ppm0.69-0.91 (m, 4H), 1.08-1.31 (m, 1H), 1.32-1.48 (m, 1H), 1.48-1.64 (m,2H), 1.64-1.81 (m, 2H), 3.17 (d, J=6.57 Hz, 2H), 3.71 (s, 2H), 3.87 (d,J=6.06 Hz, 2H), 6.94 (ddd, J=8.75, 2.43, 1.20 Hz, 1H), 7.14-7.24 (m,4H), 7.27-7.34 (m, 3H).

Example 1.27: Preparation of2-(((1r,4r)-4-(((3-Chloro-4-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 37)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and2-chloro-1-fluoro-4-iodobenzene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=450.2 [M+H]⁺.

Example 1.28: Preparation of2-(((1r,4r)-4-(((3-Fluoro-4-methylphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 38)

From tert-butyl 2-(((1r,4r)-4((phenylcarbamnyloxy)methyl)cyclohexyl)methoxy)acetate and2-fluoro-4-iodo-1-methylbenzene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=430.2 [M+H]⁺.

Example 1.29: Preparation of2-(((1r,4r)-4-(((3,5-Difluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 39)

From tert-butyl 2-(((Ir,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1,3-difluoro-5-iodobenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z: =434.3 [M+H]⁺; ¹H NMR (410 MHz, Methanol-d₆) δ ppm 0.85-1.02 (m,4H), 1.46-1.58 (m, 2H), 1.59-1.70 (m, 2H), 1.79-1.87 (m, 2H), 3.28 (d,J=6.44 Hz, 2H), 3.82 (s, 2H), 3.99 (d, J=6.19 Hz, 2H), 6.79 (tt, J=9.02,2.23 Hz, 1H), 6.88-695 (m, 2H), 7.25-7.32 (m, 2H), 7.33-7.41 (m, 1H),7.41-7.50 (m, 2H).

Example 1.30: Preparation of2-(((1r,4r)-4-(((3,4-Difluorophenylxphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 40)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1,2-difluoro-4-iodobenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=434.5 [M+H]⁺; ¹H NMR (400 MHz, Methanol-d₆) δ ppm 0.93-1.11 (m, 4H),1.52-1.68 (m, 2H), 1.67-1.81 (m, 2H), 1.84-1.98 (m, 2H), 3.36 (d, J=6.44Hz, 2H), 3.90 (s, 2H), 4.05 (d, J=6.06 Hz, 2H), 7.10-7.18 (m, 1H),7.27-7.42 (m, 5H), 7.45-7.53 (m, 2H).

Example 1.31: Preparation of2-(((1r,4r)-4-(((4-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 41)

From tert-butyl 2-(((1r,4r)-4((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-fluoro-4-iodobenzene, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=416.5 [M+H]⁺; ¹H NMR (400 MHz, Methanol-d₆) δ ppm 0.79-1.08 (m, 4H),1.45-1.60 (m, 2H), 1.61-1.73 (m, 2H), 1.77-1.89 (m, 2H), 3.29 (d, J=6.57Hz, 2H), 3.83 (s, 2H), 3.97 (d, J=6.06 Hz, 2H), 7.07-7.14 (m, 2H),7.21-7.34 (m, 5H), 7.35-7.41 (m, 2H).

Example 1.32: Preparation of2-(((1r,4r)-4-((Phenyl(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 42)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-iodo-4-methyl benzene, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=412.2 [M+H]⁺.

Example 1.33: Preparation of2-(((1r,4r)-4-((Phenyl(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 49)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and3-iodopyridine, using a similar method to the one described in Example1.21, the title compound was obtained as a white solid. LCMS m/z=399.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.67-0.91 (m, 4H), 1.31-1.47 (m,2H), 1.47-1.58 (m, 2H), 1.62-1.76 (m, 2H), 3.21-3.27 (m, 2H), 3.93 (d,J=6.06 Hz, 2H), 3.96 (s, 2H), 7.12 (d, J=7.58 Hz, 2H), 7.26-7.45 (m,3H), 7.56 (dd, J=7.96, 5.43 Hz, 1H), 8.13 (d, J=8.08 Hz, 1H), 8.36 (d,J=4.29 Hz, 1H), 8.56 (s, 1H).

Example 1.34: Preparation of2-(((1r,4r)-4-(((5-Methylthiophen-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 50)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and2-iodo-5-methylthiophene, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=418.4 [M+H]⁺.

Example 1.35: Preparation of2-(((1r,4r)-4-(((6-fluoropyridyl-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 84)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and2-fluoro-5-iodopyridine, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=417.6 [M+H]⁺.

Example 1.36: Preparation of2-(((1r,4r)-4-((Phenyl(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 85)

From tert-butyl 2-(((1r,4r)-4((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and the2-iodopyrazine, using a similar method to the one described in Example1.21, the title compound was obtained as a white solid. LCMS m/z=400.2[M+H]⁺.

Example 1.37: Preparation of2-(((1r,4r)-4-(((4-Ethoxyphenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 88)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and1-ethoxy-4-iodobenzene, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=442.1 [M+H]⁺.

Example 1.38: Preparation of2-(((1r,4r)-4-(((2-Fluoropyridin-4-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 89)

From tert-butyl 2-(((1r,4r)-4((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and2-fluoro-4-iodopyridine, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=417.6 [M+H]⁺.

Example 1.39: Preparation of2-(((1r,4r)-4-(((5-Methoxypyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 90)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and3-iodo-5-methoxypyridine, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=429.4 [M+H]⁺.

Example 1.40: Preparation of2-((1r,4r)-4-(((5-Fluoropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 91)

From tert-butyl2-(((1r,4r)-4-(phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and5-fluoro-2-iodopyridine, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=417.6 [M+H]⁺.

Example 1.41: Preparation of2-(((1r,4r)-4-((Phenyl(5-(trifluoromethyl)pyridin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 92)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and2-iodo-5-(trifluoromethyl)pyridine, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=467.5 [M+H]⁺.

Example 1.42: Preparation of2-(((1r,4r)-4-(((5-Methylpyridin-3-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 93)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and3-iodo-5-methylpyridine, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=413.2 [M+H]⁺.

Example 1.43: Preparation of2-(((1r,4r)-4-(((5-Chloropyridin-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 94)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and5-chloro-2-iodopyridine, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=433.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77-0.95 (m, 4H),1.32-1.41 (m, 1H), 1.41-1.50 (m, 1H), 1.51-1.61 (m, 2H), 1.63-1.75 (m,2H), 3.22 (d, J=6.44 Hz, 2H), 3.93 (d, J=6.06 Hz, 2H), 3.94 (s, 2H),7.21-7.32 (m, 3H), 7.36-7.44 (m, 2H), 7.70-775 (m, 1H), 7.97-8.02 (m,1H), 8.33-8.41 (m, 1H), 12.52 (bs, 1H).

Example 1.44: Preparation of2-(((1r,4r)-4-(((5-Fluoropyridin-3-yl)(phenyl)carbamoyloxy)methylcyclohexyl)methoxy)aceticAcid (Compound 95)

From tert-butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and5-fluoro-3-iodopyridine, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=417.5 [M+H]⁺.

Example 1.45: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(4-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 55) Step A: Preparation of tert-Butyl2-(((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methoxy)acetate

To a solution of (1r,4r)-cyclohexane-1,4-diyldimethanol (5.0 g, 34.7mmol) in benzene (20 mL) was added tetrabutylammonium iodide (6.40 g,17.34 mmol) and 50% aqueous NaOH (10 mL, 34.7 mmol) at room temperature.The reaction was stirred vigorously for 5 min and then tert-butyl2-bromoacetate (5.63 mL, 38.1 mmol) was added. The reaction was stirredvigorously for 2 h. The mixture was extracted with H₂O/NaOH (100 mL) andEtOAc/benzene (100 mL). The aqueous layer was extracted again with EtOAc(100 mL). The combined organic layer was dried and concentrated. Theresidue was purified by silica gel column chromatography to provide thetitle compound as a colorless oil (3.96 g). LCMS m/z=259.3 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 0.89-1.06 (m, 4H), 1.47 (s, 9H), 1.55-1.68(m, 2H), 1.76-1.98 (m, 4H), 3.32 (d, J=6.57 Hz, 2H), 3.45 (d, J=6.32 Hz,2H), 3.93 (5, 2H).

Step B: Preparation of tert-Butyl2-(((1r,4r)-4-((3-Fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate

To a solution of tert-butyl 2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (1.0 g, 3.87 mmol) and pyridine (0.438 mL,5.42 mmol) in CH₂Cl₂ (10 mL) was added 3-fluorophenyl isocyanate (0.480mL, 4.26 mmol) and the reaction was stirred at room temperatureovernight. The reaction was then heated to reflux for 5 h. After removalof the solvent, the residue was purified by silica gel columnchromatography to yield the title compound as a %% bite solid (1.12 g).LCMS m/z=340.4 [M-tert-butyl+H]⁺, ¹H NMR (400 MHz, CDCl₃) δ ppm0.85-1.04 (m, 4H), 1.41 (s, 9H), 1.51-1.64 (m, 2H), 1.69-1.87 (m, 4H),3.26 (d, J=6.32 Hz, 2H), 3.87 (s, 2H), 3.92 (d, J=6.57 Hz, 2H), 6.57 (s,1H), 6.68 (dt, J=8.34, 2.53 Hz, 1H), 6.94 (d, J=8.59 Hz; 1H), 7.13-7.18(m, 1H), 7.20-7.28 (m, 1H).

Step C: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(4-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid

From 1-iodo-4-methoxybenzene and tert-butyl2-(((1r,4r)-4-((3-fluorophenyl-carbamoyloxy)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.21, the titlecompound was obtained as a white solid. LCMS m/z=446.5 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.86 (t, J=10.11 Hz, 4H), 1.39 (s, 2H),1.54-1.62 (m, 2H), 1.64-1.74 (m, 2H), 3.23 (d, J=6.32 Hz, 2H), 3.76 (s,3H), 3.89 (d, J=6.19 Hz, 2H), 3.94 (s, 2H), 6.91-6.98 (m, 2H), 6.99-7.07(m, 2H), 7.17-7.26 (m, 3H), 7.36 (dt, J=8.18, 6.88 Hz, 1H), 12.52 (bs,1H).

Example 1.46: Preparation of2-(((1r,4r)-4-(((4-Chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 56)

From 1-chloro-4-iodobenzene and tert-butyl2-(((1r,4r)-4-((3-fluorophenyl-carbamoyloxy)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.21, the titlecompound was obtained as a white solid. LCMS m/z=450.2 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.77-0.98 (m, 4H), 1.34-1.42 (m, 1H), 1.42-1.52(m, 1H), 1.53-1.63 (m, 2H), 1.63-1.75 (try 2H), 3.23 (d, J=6.44 Hz, 2H),3.91 (d, J=6.06 Hz, 2H), 3.94 (s, 2H), 7.04-7.14 (m, 2H), 7.23-7.28 (m,1H), 7.29-7.36 (m, 2H), 7.36-7.42 (m, 1H), 7.42-7.49 (m, 2H), 12.52 (bs,1H).

Example 1.47: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 57)

From 1-fluoro-4-iodobenzene and tert-butyl 2-(((1r,4r)-4((3-fluorophenyl-carbamoyloxy)methyl)cyclohexyl)methoxy)acetate, using asimilar method to the one described in Example 1.21, the title compoundwas obtained as a white solid. LCMS m/z=434.4 [M+H]⁺.

Example 1.48: Preparation of2-(((1r,4r)-4-(((3-Chlorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 58)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-chloro-3-iodobenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSto z=450.2 [M+H]⁺.

Example 1.49: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 59)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-iodo-3-methylbenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=430.5 [M+H]⁺.

Example 1.50: Preparation of2-(((1r,4r)-4-(((4-Chloro-3-fluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 60)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-chloro-2-fluoro-4-iodobenzene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=468.5 [M+H]⁺.

Example 1.51: Preparation of2-(((1r,4r)-4-(((3-Chloro-4-fluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 61)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 2-chloro-1-fluoro-4-iodobenzene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=468.4 [M+H]⁺.

Example 1.52: Preparation of2-(((1r,4r)-4-(((3-Fluoro-4-methylphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 62)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 2-fluoro-4-iodo-1-methylbenzene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid (17.4 mg). LCMS m z=448.2 [M+H]⁺.

Example 1.53: Preparation of2-(((1r,4r)-4-(((3,5-Difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 64)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1,3-difluoro-5-iodobenzene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=452.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77-0.94(m, 4H), 1.32-1.42 (m, J=3.41 Hz, 1H), 1.42-1.52 (m, 1H), 1.52-1.60 (m,2H), 1.64-1.76 (m, 2H), 3.23 (d, J=6.32 Hz, 2H), 3.92 (d, J=5.94 Hz,2H), 3.94 (s, 2H), 7.07-7.21 (m, 5H), 7.32 (dt, J=10.36, 2.27 Hz, 1H),7.45 (td, J=8.18, 6.76 Hz, 1H), 12.53 (bs, 1H).

Example 1.54: Preparation of2-(((1r,4r)-4-(((3,4-Difluorophenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 65)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1,2-difluoro-4-iodobenzene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=452.1 [M+H]⁺.

Example 1.55: Preparation of2-(((1r,4r)-4-((Bis(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 66)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-fluoro-3-iodobenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=434.4 [M+H]⁺.

Example 1.56: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(3-methoxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 67)

From tert-butyl 2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate and 1-iodo-3-methoxybenzene, using asimilar method to the one described in Example 1.21, the title compoundwas obtained as a white solid. LCMS m/z=446.4 [M+H]⁺.

Example 1.57: Preparation of2-(((1r,4r)-4-(((3,5-Dimethylphenyl)(3-fluorophenyl)carbamoyloxy)methylcyclohexyl)methoxy)aceticAcid (Compound 68)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-iodo-3,5-dimethylbenzene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=444.7 [M+H]⁺.

Example 1.58: Preparation of2-(((1r,4r)-4-(((3-fluorophenyl)(p-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 69)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-iodo-4-methylbenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=430.3 [M+H]⁺.

Example 1.59: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(6-fluoropyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 70)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 5-fluoro-2-iodopyridine, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=435.3 [M+H]⁺.

Example 1.60: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(5-methylthiophen-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 71)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 2-iodo-5-methylthiophene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=436.3 [M+H]⁺.

Example 1.61: Preparation of2-(((1r,4r)-4-(((4-Ethoxyphenyl)(3-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 72)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-ethoxy-4-iodobenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=460.5 [M+H]⁺.

Example 1.62: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(3-(trifluoromethoxy)phenyl)carbamoyloxyknethyl)cyclohexyl)methoxy)aceticAcid (Compound 73)

From tert-butyl2-(((1r,4r)-4-(3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-iodo-3-(trifluoromethoxy)benzene, using a similar method to theone described in Example 1.21, the title compound was obtained as awhite solid. LCMS m/z: =500.5 [M+H]⁺.

Experiment 1.63: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 74)

From tert-butyl2-(((1r,4r)-4-(3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 3-iodopyridine, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=417.4 [M+H]⁺.

Experiment 1.64: Preparation of2-(((1r,4r)-4-(((3-Fluorophenyl)(pyrazin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 75)

From tert-butyl2-(((1r,4r)-4-((3-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 2-iodopyrazine, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=418.5 [M+H]⁺.

Example 1.65: Preparation of2-(((1r,4r)-4-(((4-Chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 76) Step A: Preparation of Methyl4-Fluoro-2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)phenylcarbamate

4-Fluorophenyl isocyanate (4.75 g, 34.7 mmol),(1r,4r)-cyclohexane-1,4-diyldimethanol (5.0 g, 34.7 mmol), and pyridine(3.93 mL, 48.5 mmol) were dissolved in CH₂Cl₂ (30 mL). The reactionmixture was stirred at room temperature overnight. After removal of thesolvent, the residue was purified by silica gel column chromatography toyield the title compound as a white solid (4.92 g). LCMS m/z=282.4[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-1.07 (m, 4H), 125-1.38 (m,1H), 1.49-1.64 (m, 1H), 1.72-1.82 (m, 4H), 3.19-3.24 (m, 2H), 3.89 (d,J=6.57 Hz, 2H), 4.34 (t, J=5.31 Hz; 1H), 7.06-7.15 (m, 2H), 7.46 (dd,J=8.97, 4.93 Hz, 2H), 9.61 (s, 1H).

Step B: Preparation of tert-Butyl2-(((1r,4r)-4-((4-Fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate

To a solution of methyl4-fluoro-2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)phenylcarbamate (2.0 g,7.11 mmol) and rhodium(II) acetate dimer (0.157 g, 0.355 mmol) in CH₂Cl₂(10 mL) was added slowly tert-butyl 2-diazoacetate (1.084 mL, 7.82 mmol)pre-dissolved in CH₂Cl₂ (5 mL) via an addition funnel at 0° C. Thereaction was stirred at 0° C. for 1 h and stirred at room temperaturefor another 1 h. After removal of the solvent, the residue was purifiedby silica gel column chromatography to yield the title compound as a tansolid (1.9 g). LCMS m/z=340.4 [M-tert-butyl+H]⁺, 396.2 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.97 (d, J=10.36 Hz, 4H), 1.42 (s, 9H),1.44-1.53 (m, 1H), 1.54-1.64 (m, 1H), 1.72-1.82 (m, 4H), 3.26 (d, J=6.32Hz, 2H), 3.90 (d, J=6.57 Hz, 2H), 3.92 (s, 2H), 7.06-7.15 (m, 2H), 7.46(dd, J=8.84, 4.93 Hz, 2H), 9.61 (s, 1H).

Step C: Preparation of2-(((1r,4r)-4-(((4-Chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid

From tert-butyl2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-chloro-4-iodobenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=450.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78-0.94 (m, 4H),1.33-1.52 (m, J=29.68 Hz, 2H), 1.53-1.62 (m, 2H), 1.64-1.74 (m, 2H),3.23 (d, J=6.32 Hz, 2H), 3.89 (d, J=6.06 Hz, 2H), 3.93 (s, 2H),7.17-7.27 (m, 2H), 7.27-7.39 (m, 4H), 7.39-7.50 (m, 2H), 12.51 (bs, 1H).

Example 1.66: Preparation of2-(((1r,4r)-4-(((4-Fluorophenyl)(5-methylthiophen-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 77)

From tert-butyl2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 2-iodo-5-methylthiophene, using a similar method to the onedescribed in Example 1.21, the title compound was obtained as a whitesolid. LCMS m/z=436.4 [M+H]⁺.

Example 1.67: Preparation of2-(((1r,4r)-4-(((3-Chlorophenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 78)

From tert-butyl2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-chloro-3-iodobenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=450.0 [M+H]⁺.

Example 1.68: Preparation of2-(((1r,4r)-4-(((4-fluorophenyl)(pyridin-3-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 79)

From tert-butyl2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 3-iodopyridine, using a similar method to the one described inExample 1.21, the title compound was obtained as a white solid. LCMSm/z=417.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79-0.94 (m, J=10.57,10.57, 10.57 Hz, 4H), 1.31-1.43 (m, 1H), 1.42-1.52 (m, 1H), 1.52-1.63(m, 2H), 1.64-1.78 (m, 2H), 3.23 (d, J==6.44 Hz, 2H), 3.92 (d, J=5.94Hz, 2H), 3.95 (s, 2H), 7.20-7.30 (m, 2H), 7.39-7.46 (m, 2H), 7.49 (dd,J=8.27, 4.86 Hz, 1H), 7.77-7.84 (m, 1H), 8.46 (dd, J=4.86, 1.45 Hz, 1H),8.62 (d, J=2.15 Hz, 1H).

Example 1.69: Preparation of2-(((1r,4r)-4-(((4-Ethoxyphenyl)(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 80)

From tert-butyl2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-ethoxy-4-iodobenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=460.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79-0.94 (m, 4H),1.31 (t. J=6.95 Hz, 3H), 1.34-1.50 (m, 2H), 1.51-1.64 (m, 2H), 1.64-1.76(m, 2H), 3.23 (d, J=6.44 Hz, 2H), 3.86 (d, J=6.19 Hz, 2H), 3.94 (s, 2H),4.00 (y, J=6.95 Hz, 2H), 6.85-6.95 (m, 2H), 7.11-7.25 (m, 4H), 7.28-7.36(m, 2H), 12.53 (s, 1H).

Example 1.70: Preparation of2-(((1r,4r)-4-(((4-Fluorophenyl)(4-(trifluoromethoxy)phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 81)

From tert-butyl2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-iodo-4-(trifluoromethoxy)benzene, using a similar method to theone described in Example 1.21, the title compound was obtained as awhite solid. LCMS m/z=500.5 [M+H]⁺.

Example 1.71: Preparation of2-(((1r,4r)-4-(((4-Fluorophenyl)(m-tolyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 82)

From tert-butyl2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-iodo-3-methylbenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=430.5 [M+H]⁺.

Example 1.72: Preparation of2-(((1r,4r)-4-((Bis(4-fluorophenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 83)

From tert-butyl2-(((1r,4r)-4-((4-fluorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetateand 1-fluoro-4-iodobenzene, using a similar method to the one describedin Example 1.21, the title compound was obtained as a white solid. LCMSm/z=434.5 [M+H]⁺.

Example 1.73: Preparation of2-(((1r,4r)-4-((Phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetic Acid(Compound 29)

tert-Butyl2-(((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate(20.0 mg, 0.053 mmol) was dissolved in HCl (4 M in dioxane) (397 μL.,1.590 mmol). The reaction was stirred at room temperature overnight. Thesolvent was removed and the residue was purified by preparative LCMS toyield the title compound as a white solid (9.2 mg). LCMS m/z=322.4[M+H]⁺.

Example 1.74: Preparation of2-(((1r,4r)-4-(((3-Chloro-5-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxyy)aceticAcid (Compound 46)

From 1-bromo-3-chloro-5-fluorobenzene, using a similar method to the onedescribed in Example 1.18, the title compound was obtained as a lightbrown oil. LCMS m/z=450.2 [M+H]⁺.

Example 1.75: Preparation of2-(((1r,4r)-4-((Phenyl(pyridin-2-yl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 63)

From N-phenylpyridin-2-amine, using a similar method to the onedescribed in Example 1.18 (Steps B and C), the title compound wasobtained as a colorless oil. LCMS m/z=399.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.77-0.93 (m, 4H), 1.32-1.41 (m, 1H), 1.41-1.49 (m,J=3.28 Hz, 1H), 1.50-1.63 (m, J=7.20 Hz, 2H), 1.62-1.77 (m, J=7.33 Hz,2H), 3.22 (d, J=6.32 Hz, 2H), 3.92 (d, J=6.06 Hz, 2H), 3.94 (s, 2H),7.19-7.29 (m, 4H), 7.33-7.41 (m, 2H), 7.60 (d, J=8.21 Hz, 1H), 7.83-7.91(m, 1H), 8.31-8.38 (m, 1H).

Example 1.76: Preparation of2-(((1r,4r)-4-(((5-Methylthiazol-2-yl)(phenyl)carbamoyloxy)methyl(cyclohexyl)methoxy)aceticAcid (Compound 97) Step A: Preparation of 2-Iodo-5-methylthiazole

5-Methylthiazole (179 μL, 2.017 mmol) was dissolved in THF (5 mL). Thesolution was cooled in a dry ice/acetone bath (−70° C.) and LDA (1.8 Min heptane/THF/ethylbenzene, 1233 μL, 2.219 mmol) was added slowly viasyringe. The reaction was stirred at −70° C. for 30 min. Iodine (614 mg,2.420 mmol) pre-dissolved in THF (2 mL) was added slowly via syringe.The reaction was warmed to room temperature, stirred for 1 h, andquenched with H₂O (5 mL). The mixture was extracted with H₂O (20 mL) andEtOAc (20 mL). The aqueous layer was extracted again with EtOAc (20 mL).The combined organic layers were dried, concentrated, and the residuewas purified by silica gel column chromatography to provide the titlecompound as a light brown oil (61 mg). LCMS m/z=226.1 [M+H]⁺.

Step B: Preparation of2-(((1r,4r)-4-(((5-Methylthiazol-2-yl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid

From 2-iodo-5-methythiazole and tert-butyl2-((1r,4r)-4-((phenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate,using a similar method to the one described in Example 1.21, the titlecompound was obtained as a light brown oil. LCMS m/z=419.5 [M+H]⁺.

Example 1.77: Preparation of Sodium2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate

From 3-fluoro-N-phenylaniline, using a similar method to the onedescribed in Example 1.19, the sodium salt of the title compound wasobtained as a white solid. LCMS m/z=416.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.71-0.93 (m, 4H), 1.34 (bs, 1H), 1.44 (bs, 1H),1.54-1.57 (m, 2H), 1.65-1.69 (m, 2H), 3.15 (d, J=6.57 Hz, 2H), 3.44 (s,2H), 3.90 (d, J=5.94 Hz; 2H), 7.02-7.11 (m, 2H), 7.22 (dt, J=10.67, 2.24Hz, 1H), 7.25-7.33 (m, 3H), 7.34-7.44 (m, 3H).

Example 1.78: Preparation of2-(((1r,4r)-4-((3,3-Diphenylureido)methyl)cyclohexyl)methoxy)acetic Acid(Compound 2) Step A: Preparation of tert-Butyl2-(((1r,4r)-4-((tert-Butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate

A cooled solution of tert-butyl((1r,4r)-4-(hydroxymethyl)cyclohexyl)methylcarbamate (2.0 g, 8.22 mmol)in THF (30 mL) was treated with NaH (60% dispersion in mineral oil,1.315 g, 32.9 mmol). The resulting suspension was stirred at roomtemperature for 1 h then tert-butyl 2-bromoacetate (1.822 mL, 12.33mmol) was added. The reaction was heated in the microwave to 60° C. for1 h and then left stirring overnight at room temperature. Additionaltert-butyl 2-bromoacetate (975 μL) was added and the reaction was heatedto 60° C. and stirred for 2 h. The reaction was quenched with water andextracted with DCM. The combined DCM extract was washed with water;dried over MgSO₄ and concentrated. The resulting residue was purified bypreparative LCMS to provide the title compound as a white solid (0.250g). LCMS m/z=380.4 [M+Na]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78-0.96(m, 4H), 1.29 (bs, 1H), 1.39 (s, 9H), 1.44 (s, 9H), 1.66-1.79 (m, 4H),2.78 (t, J=6.32 Hz, 2H), 326 (d, J=6.32 Hz, 2H), 3.94 (s, 2H), 6.80 (t,J=5.68 Hz, 1H).

Step B: Preparation of2-(((1r,4r)-4-(Aminomethyl)cyclohexyl)methoxy)acetic Acid

tert-Butyl2-(((1r,4r)-4-((tert-butoxycarbonylamino)methyl)cyclohexyl)methanyl)acetate(61 mg, 0.171 mmol) was treated with 4.0 M HCl in dioxane (5.00 mL, 165mmol) at room temperature for 1 h, followed by heating at 60° C. for 45min. The solvent was evaporated and the resulting residue was washed 3×with DCM and concentrated to yield the title compound as an off whitesolid (40 mg) without further purification. LCMS m/z=202.4 [M+H]⁺.

Step C: Preparation of2-(((1r,4r)-4-((3,3-Diphenylureido)methyl)cyclohexyl)methoxy)acetic Acid(Compound 2)

A solution of 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid(39.1 mg, 0.194 mmol) in THF (2 mL) was treated with potassiumtert-butoxide (0.583 mL, 0.583 mmol). Diphenylcarbamic chloride (45 mg,0.194 mmol) was added and the resulting solution was stirred at roomtemperature for 45 min. The reaction was quenched with water. The waterlayer was concentrated under reduced pressure. The residue was purifiedby preparative LCMS. The appropriate fractions were collected. Afterremoval of the solvent, the residue was dissolved in MeOH (2.0 mL) andto this mixture was added 0.5 M sodium methoxide in MeOH (0.388 mL,0.194 mmol). The solution was stirred at room temperature for 1 h. Afterremoval of the solvent, the residue was dissolved in minimal amount of1:1 H₂O/The solution, frozen and lyophilized to provide the titlecompound (32 mg). LCMS m/z=397.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.69-0.87 (m, 4H), 1.25-1.43 (m, 2H), 1.53-1.70 (m, 4H), 2.83 (t, J=6.19Hz, 2H), 3.18 (d, J=6.32 Hz, 2H), 3.89 (s, 2H), 5.88 (t, J=5.68 Hz, 1H),7.05-7.14 (m, 6H), 7.28 (t, J=7.83 Hz, 4H).

Example 1.79: Preparation of2-(((1r,4r)-4-((3-Benzhydrylureido)methyl)cyclohexyl)methoxy)acetic Acid(Compound 1)

A solution of 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid(20.0 mg, 0.099 mmol) in DMF was treated with TEA (0.021 mL, 0.149 mmol)followed by (isocyanatomethylene)dibenzene (0.019 mL, 0.099 mmol); theresulting solution was stirred at room temperature for 1.0 h. Thereaction was stopped and the reaction mixture was purified bypreparative LCMS to provide the title compound as a white solid (9.0mg). LCMS m/z=411.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.97(m, 4H), 1.27 (bs, 1H), 1.47 (bs, 1H), 1.66-1.79 (m, 4H), 2.89 (t,J=6.06 Hz, 2H), 3.27 (d, J=6.32 Hz, 2H), 3.98 (s, 2H), 5.89 (d, J=8.34Hz, 1H), 5.96 (t, J=5.68 Hz, 1H), 6.80 (d, J=8.59 Hz, 1H), 7.21-7.29 (m,6H), 7.31-7.37 (m, 4H), 12.57 (bs, 1H).

Example 1.80: Preparation of2-(((1r,4r)-4-((3-(3-Methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticacid (Compound 17) Step A: Preparation of3-Methoxyphenyl(phenyl)carbamic Chloride

To a cooled solution of 3-methoxy-N-phenylaniline (100.0 mg, 0.502 mmol)and pyridine (0.102 mL, 1.267 mmol) in DCM (500 mL) was addedtriphosgene (120.0 mg, 0.406 mmol). The solution was allowed to warm upto room temperature and stirred overnight. The organic solvent wasevaporated. The residue was dissolved in ethyl acetate, washed withwater, brine, dried over MgSO₄ and concentrated to provide the titlecompound (105.0 mg). LCMS m/z=261.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 3.79 (s, 3H), 6.90-7.31 (m, 3H), 7.32-7.52 (m, 4H), 7.52-7.70 (m,2H).

Step B: Preparation of tert-Butyl2-(((1r,4r)-4-((tert-Butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate

To a solution of tert-butyl((1r,4r)-4-(hydroxymethyl)cyclohexyl)methylcarbamate (1.0 g, 4.11 mmol)and rhodium(II) acetate (0.091 g, 0.205 mmol) in dichloromethane (10 mL)was added dropwise a solution of tert-butyl 2-diazoacetate (0.584 g,4.11 mmol) in dichloromethane (10 mL). The resulting solution wasstirred at room temperature overnight. The reaction was quenched withwater; the organic layer was subsequently washed with water (twice) andbrine; dried over MgSO₄ and concentrated. The residue was purified bypreparative LCMS to provide the title compound as a white solid (571mg). LCMS m/z=380.4 [M+Na]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78-0.97(m, 4H), 1.29 (bs, 1H), 1.39 (s, 9H), 1.44 (s, 9H), 1.66-1.79 (m, 4H),2.78 (t, J=6.32 Hz, 2H), 3.26 (d, J=6.32 Hz, 2H), 3.94 (s, 2H), 6.80 (t,J=5.68 Hz, 1H).

Step C: Preparation of tert Butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate

tert-Butyl2-(((1r,4r)-4-((tert-butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate(61.0 mg; 0.171 mmol) was treated with HCl (4.0 M in dioxane, 3.0 mL)and stirred at room temperature for 1 h. The mixture was concentrated toprovide the title compound without further purification. LCMS m/z=258.4[M+H]⁺.

Step D: Preparation of2-(((1r,4r)-4-((3-(3-Methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 17)

To tert-butyl 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate(25.3 mg, 0.098 mmol) in a 5 mL microwave reaction vial were added DCM(1.0 mL) and TEA (0.036 mL, 0.262 mmol). The solution was stirredbriefly then 3-methoxyphenyl(phenyl)carbamic chloride (17.0 mg, 0.065mmol) was added in three portions. The resulting solution was heatedunder microwave irradiation at 80° C. 2 h. The reaction mixture wasconcentrated and the residue was treated with HCl (4.0 M in dioxane, 3mL) at 60° C. for 1 h. The mixture was concentrated and the residue waspurified by preparative LCMS to provide the title compound as a whitesolid (8.0 mg). LCMS m/z=427.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.68-0.88 (m, 4H), 1.25-1.43 (m, 2H), 1.54-1.70 (m, 4H), 2.83 (t, J=6.19Hz, 2H), 3.17 (d, J=6.57 Hz, 2H), 3.65 (s, 3H), 3.89 (s, 2H), 5.96 (t,J=5.81 Hz, 1H), 6.63 (dd, J=7.83, 1.52 Hz, 1H), 6.68 (t, J=2.15 Hz, 1H),6.72 (dd, J=8.21, 2.40 Hz, 1H), 7.06-7.13 (m, 3H), 7.19 (t, J=8.08 Hz,1H), 7.27 (t, J=7.71 Hz, 2H), 12.50 (bs, 1H).

Example 1.81: Preparation of2-(((1r,4r)-4-((3,3-di-p-Tolylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 15)

From di-p-tolyl carbamic chloride and tert-butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a similarmethod to the one described in Example 1.80, Step D, the title compoundwas obtained as a white solid. LCMS m/z=425.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.66-0.88 (m, 4H), 1.23-1.43 (m, 2H), 1.52-1.72 (m, 4H),2.20 (s, 6H), 2.81 (t, J=6.32 Hz, 2H), 3.17 (d, J=6.32 Hz, 2H), 3.89 (s,2H), 5.76 (t, J=5.81 Hz, 1H), 6.96 (d, J=8.34 Hz, 4H), 7.07 (d, J=8.08Hz, 4H), 12.50 (bs, 1H).

Example 1.82: Preparation of2-(((1r,4r)-4-((3,3-di-ne-Tolylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 16)

From di-m-tolyl carbamic chloride and tert-butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a similarmethod to the one described in Example 1.80, Step D, the title compoundwas obtained as a white solid. LCMS m/z=425.3 [M+H]⁺.

Example 1.83: Preparation of2-(((1r,4r)-4-((3-(4-Methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 18)

From 4-methoxyphenyl(phenyl)carbamic chloride and tert-butyl2-(((1r,4r)-4 (aminomethyl)cyclohexyl)methoxy)acetate, using a similarmethod to the one described in Example 1.80, Step D, the title compoundwas obtained as a white solid. LCMS m/z=427.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.66-0.87 (m, 4H), 1.23-1.43 (m, 2H), 1.51-1.70 (m, 4H),2.81 (t, J=6.19 Hz; 2H), 3.17 (d, J=6.32 Hz, 2H), 3.68 (s, 3H), 3.89 (s,2H), 5.77 (t, J=5.68 Hz, 1H), 6.88 (d, J=8.84 Hz, 2H), 7.04-7.10 (m,5H), 7.22 (t, J=7.83 Hz, 2H), 12.50 (bs, 1H).

Example 1.84: Preparation of2-(((1r,4r)-4-((3-(4-Methoxy-2-methylphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 19)

From 4-methoxy-2-methylphenyl(phenyl)carbamic chloride and tert-butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a similarmethod to the one described in Example 1.80, Step D, the title compoundwas obtained as a white solid. LCMS m/z=441.3 [M+H]⁺.

Example 1.85: Preparation of2-(((1r,4r)-4-((3-Phenyl-3-(3-(trifluoromethyl)phenyl)ureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 20)

From phenyl(3-(trifluoromethyl)phenyl)carbamic chloride and tert-butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a similarmethod to the one described in Example 1.80, Step D, the title compoundwas obtained as a white solid. LCMS m/z=465.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.68-0.87 (m, 4H), 1.26-1.43 (m, 2H), 1.54-1.71 (m, 4H),2.84 (t, J=6.19 Hz, 2H), 3.18 (d, J=6.32 Hz, 2H), 3.89 (s, 2H), 6.23 (t,J=5.68 Hz, 1H), 7.16 (d, J=7.58 Hz, 2H), 7.21-7.27 (m, 2H), 7.33-7.49(m, 5H), 12.50 (bs, 1H).

Example 1.86: Preparation of2-(((1r,4r)-4-((3-(3-Fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 3) Step A: Preparation of 3-Fluoro-N-phenylaniline

In a round bottom flask equipped with a condenser was placedN-phenylacetamide (1.0 g, 7.40 mmol), copper (I) chloride (0.146 g,1.480 mmol), potassium carbonate (1.329 g, 9.62 mmol),1-bromo-3-fluorobenzene (1.942 g, 11.10 mmol) and xylene (5 mL). Thesuspension was heated to 180° C. and refluxed for 66 h. The suspensionwas filtered; and the filtrate was concentrated. The dark brown residuewas dissolved in ether; filtered; and the filtrate was concentrated. Thedark brown residue was dissolved in ethanol (10.00 mL), treated withpotassium hydroxide (1.909 g, 34.0 mmol) and refluxed for 2 h. Thesolution was poured into of water (80 mL) and extracted with DCM. Thecombined DCM extract was washed with water (6×), dried over MgSO₄ andconcentrated to afford the title compound as a dark brown solid (0.669g,). LCMS m/z: =188.2 [M+H]⁺.

Step B: Preparation of 3-Fluorophenyl(phenyl)carbamic Chloride

From 3-fluoro-N-phenylaniline, using a similar method to the onedescribed in Example 1.80, Step A, the title compound was obtained as abrown oil. LCMS m/z=250.2 [M+H]⁺.

Step C: Preparation of2-(((1r,4r)-4-((3-(3-Fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 3)

From 3-fluorophenyl(phenyl)carbamic chloride and tert-butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a similarmethod to the one described in Example 1.80, Step D, the title compoundwas obtained as a white solid. LCMS m/z=415.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.78-0.97 (m, 4H), 0.89-0.96 (m, 2H), 1.34-1.54 (m, 2H),1.64-1.80 (m, 4H), 2.93 (t, J=6.25 Hz, 2H), 3.27 (d, J=6.44 Hz, 2H),3.98 (s, 2H), 6.12 (t, J=5.81 Hz, 1H), 6.91 (ddd, J=8.08, 1.96, 0.82 Hz,1H), 6.96-7.05 (m, 2H), 7.22 (dd, J=8.46, 1.14 Hz, 2H), 7.26-7.39 (m,2H), 7.43 (t, J=7.83 Hz, 2H), 12.55 (bs, 1H).

Example 1.87: Preparation of2-(((1r,4r)-4-((3-(3-Chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 6)

To a solution of 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)aceticacid (24.96 mg, 0.124 mmol) in THE (1.5 mL) was added potassiumtert-butoxide (50.6 mg, 0.451 mmol). The solution was stirred brieflythen 3-chlorophenyl(phenyl)carbamic chloride (30 mg, 0.113 mmol) wasadded. The resulting solution was stirred at room temperature for 1 h.The reaction was quenched with water. The aqueous layer was concentratedunder vacuum. The residue was purified by preparative LCMS to providethe title compound as a white solid (5.0 mg). LCMS m/z=431.3 [M+H]⁺.

Example 1.88: Preparation of2-(((1r,4r)-4-((3-(4-Fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 8)

From 4-fluorophenyl(phenyl)carbamic chloride and2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid, using asimilar method to the one described in Example 1.87, the title compoundwas obtained as a white solid. LCMS m/z=415.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.66-0.88 (m, 4H), 1.24-1.43 (m, 2H), 1.54-1.71 (m, 4H),2.83 (t, J=6.25 Hz, 2H), 3.18 (d, J=6.44 Hz, 2H), 3.88 (s, 2H), 5.88 (t,J=5.75 Hz, 1H), 7.06-7.17 (m, 7H), 7.28 (t, J=7.77 Hz, 2H), 12.41 (bs,1H).

Example 1.89: Preparation of2-(((1r,4r)-4-((3-(2-Fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 10)

From 2-fluorophenyl(phenyl)carbamic chloride and2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid, using asimilar method to the one described in Example 1.87, the title compoundwas obtained as a white solid. LCMS m/z=415.5 [M+H]⁺.

Example 1.90: Preparation of2-(((1r,4r)-4-((3-(4-Chlorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 11)

From 4-chlorophenyl(phenyl)carbamic chloride and2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid, using asimilar method to the one described in Example 1.87, the title compoundwas obtained as a white solid. LCMS m/z=431.2 [M+H]⁺; ¹H NMR (400 MHz;DMSO-d₆) δ ppm 0.77-1.01 (m, 4H), 1.34-1.55 (m, 2H), 1.63-1.85 (m, 4H),2.92 (t, J=5.87 Hz, 2H), 3.28 (d, J=6.44 Hz, 2H), 3.98 (s, 2H), 5.88 (t,J=5.75 Hz, 1H), 7.13-7.29 (m, 5H), 7.36-7.45 (m, 4H).

Example 1.91: Preparation of 2-(((1r,4r)-4-((3-Phenyl-3-nomtolylureido)methyl)cyclohexyl)methoxy)acetic Acid (Compound 12)

From phenyl(m-tolyl)carbamic chloride and2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid, using asimilar method to the one described in Example 1.87, the title compoundwas obtained as a white solid. LCMS m/z=411.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.77-0.98 (m, 4H), 1.34-1.54 (m, 2H), 1.63-1.81 (m, 4H),2.29 (s, 3H), 2.93 (t, J=6.32 Hz, 2H), 3.28 (d, J=6.44 Hz, 2H), 3.98 (s,2H), 5.89 (t, J=5.81 Hz, 1H), 6.98 (d, J=7.96 Hz, 1H), 7.05 (d, J=8.21Hz, 2H), 7.13-7.22 (m, 3H), 7.27 (t, J=7.71 Hz, 1H), 7.33-7.39 (m, 2H),12.51 (bs, 1H).

Example 1.92: Preparation of 2-(((1r,4r)-4-((3-Phenyl3-p-tolylureido)methyl)cyclohexyl)methoxy)acetic Acid (Compound 13)

From phenyl(p-tolyl)carbamic chloride and2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetic acid, using asimilar method to the one described in Example 1.87, the title compoundwas obtained as a white solid. LCMS m/z=411.5 [M+H]⁺.

Example 1.93: Preparation of2-(((1r,4r)-4-((3-(3,5-Difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 44) Step A: Preparation of 3,5-Difluoro-N-phenylaniline

In a 5 mL microwave reaction vial was placed aniline (0.298 g, 3.20mmol) and 1,3-difluoro-5-iodobenzene (0.768 g, 3.20 mmol) in toluene (3mL), KOH (0.323 g, 5.76 mmol) in water (650 μL) andN,N,N-trimethylhexadecan-1-aminium bromide (6.30 mg, 0.017 mind) wereadded to the vial with stirring. After the reaction was warmed to 90°C., bis[tri(t-butylphosphine]palladium[0] (0.016 g, 0.032 mmol) wasadded and the reaction was stirred at 150° C. for 4 h and then 160° C.for 2 h. The mixture was diluted with water and brine, and extractedwith toluene. The toluene extract was subsequently washed with water,dried over MgSO₄ and concentrated. The residue was purified by flashcolumn chromatography to provide the title compound as a brown oil(0.132 g). LCMS m/z=206.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.54(tt, J=9.35, 2.27 Hz, 1H), 6.63 (dd, J=10.48, 2.15 Hz, 2H), 7.01 (dt,J=14.65, 1.14 Hz, 1H), 7.17 (dd. J=8.59, 1.01 Hz, 2H), 7.34 (t, J=7.83Hz; 2H), 8.69 (s, 1H).

Step B: Preparation of 3,5-Difluorophenyl(phenyl)carbamic Chloride

From 3,5-difluoro-N-phenylaniline, using a similar method to the onedescribed in Example 1.80, Step A, the title compound was obtained as abrown oil. LCMS m/z=268.7 [M+H]⁺.

Step C: Preparation of2-(((1r,4r)-4-((3-(3,5-Difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticacid (Compound 44)

From 3,5-difluorophenyl(phenyl)carbamic chloride and tert-butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a similarmethod to the one described in Example 1.80, Step D, the title compoundwas obtained as a white solid. LCMS m/z=433.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.77-0.97 (m, 4H), 1.35-1.53 (m, 2H), 1.62-1.79 (m, 4H),2.92 (t, J=6.19 Hz, 2H), 3.27 (d, J=6.32 Hz, 2H), 3.98 (s, 2H), 6.32 (t,J=5.56 Hz, 1H), 6.76-6.84 (m, 2H), 6.96-7.04 (m, 1H), 7.26 (d, J=7.33Hz, 2H), 7.33-7.40 (m, 1H), 7.48 (t, J=7.71 Hz, 2H).

Example 1.94: Preparation of2-(((1r,4r)-4-((3-(2,3-Difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticacid (Compound 43)

From 2,3-difluorophenyl(phenyl)carbamic chloride and tert-butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a similarmethod to the one described in Example 1.80, Step D, the title compoundwas obtained as a white solid. LCMS m/z=433.4 [M+H]⁺.

Example 1.95: Preparation of2-(((1r,4r)-4-((3-(3-Chloro-2-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 45)

From 3-chloro-2-fluorophenyl(phenyl)carbamic chloride and tert-butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a similarmethod to the one described in Example 1.80, Step D, the title compoundwas obtained as a white solid. LCMS m/z=449.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.78-0.97 (m, 4H), 1.34-1.53 (m, 2H), 1.64-1.80 (m, 4H),2.92 (t, J=5.94 Hz, 2H), 3.27 (d, J=6.32 Hz, 2H), 3.98 (s, 2H), 6.51 (t,J=5.56 Hz, 1H), 7.16-7.30 (m, 5H), 7.38 (t, J=7.20 Hz, 2H), 7.50-7.56(m, 1H).

Example 1.96: Preparation of2-(((1r,4r)-4-((3-(3-Chloro-5-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 47)

From 3-chloro-5-fluorophenyl(phenyl)carbamic chloride and tert-butyl2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate, using a similarmethod to the one described in Example 1.80, Step D, the title compoundwas obtained as a white solid. LCMS m/z=449.2 [M+H]⁺.

Example 1.97: Preparation of 2-(((1r,4r)-4-((3-(2-Fluoro3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)acetic Acid(Compound 53) Step A: Preparation of 2-Fluoro-3-methoxy-N-phenylaniline

In a reaction vial were placed aniline (0.200 g, 2.182 mmol);2-fluoro-1-iodo-3-methoxybenzene (0.500 g., 1.984 mmol), Pd₂(dba)₃(0.091 g, 0.099 mmol), BINAP (0.185 g, 0.298 mmol), NaOtBu (0.286 g,2.98 mmol), and toluene (3 mL). The reaction was stirred at 80° C.overnight and quenched with water. The organic layer was separated andconcentrated. The residue was purified by flash column chromatography toprovide the title compound as a brown oil (0.313 g). LCMS m/z=218.4[M+H]⁺; ¹H NMR (400 MHz DMSO-d₆) δ ppm 3.82 (s, 3H), 6.73 (ddd, J=10.93,8.15, 1.64 Hz, 1H), 6.88-7.05 (m, 3H), 7.15 (d, J=7.33 Hz, 2H),7.25-7.31 (m, 2H), 7.80 (s, 1H).

Step B: Preparation of 2-Fluoro-3-methoxyphenyl(phenyl)carbamic Chloride

From 2-fluoro-3-methoxy-N-phenylaniline, using a similar method to theone described in Example 1.80, Step A, the title compound was obtainedas a brown oil. LCMS m/z=280.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-4) δ ppm3.98 (s, 3H), 7.12-7.24 (m, 1H), 7.33-7.53 (m, 6H), 7.59 (d, J=7.33 Hz,1H).

Step C: Preparation of Ethyl2-(((1r,4r)-4-((tert-Butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate

To a solution of tert-butyl((1r,4r)-4-(hydroxymethylcyclohexyl)methylcarbamate (500 mg, 2.055 mmol)and rhodium(II) acetate (45.4 mg, 0.103 mmol) in DCM (5.0 mL) was addeddropwise a solution of ethyl 2-diazoacetate (0.213 mL, 2.055 mmol) inDCM (10 mL). The resulting solution was stirred at room temperatureovernight. The reaction was quenched with water; the organic layer waswashed with water (twice) and brine, dried over MgSO₄ and concentrated.The residue was purified by preparative LCMS to provide the titlecompound as a white solid. (244 mg). LCMS m/z=330.2 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.78-0.97 (m, 4H), 1.22 (t, J=7.07 Hz, 3H), 1.29(bs, 1H), 1.39 (s, 9H), 1.48 (bs, 1H), 1.66-1.79 (m, 4H), 2.78 (t,J=6.32 Hz, 2H), 3.28 (d, J=6.57 Hz, 2H), 4.07 (s, 2H), 4.13 (q, J=7.07Hz, 2H), 6.81 (t, J=5.81 Hz, 1H).

Step D: Preparation of Ethyl2-(((1r,4r)-4-(Aminomethyl)cyclohexyl)methoxy)acetate

In a round-bottomed flask ethyl2-(((1r,4r)-4-((tert-butoxycarbonylamino)methyl)cyclohexyl)methoxy)acetate(244 mg, 0.741 mmol) was treated with HCl (4.0 M in dioxane, 4.0 mL) andthe mixture was stirred for 30 min at room temperature. The mixture wasconcentrated under reduced pressure and the residue was dried in avacuum oven overnight to afford the title compound (110 mg) withoutfurther purification. LCMS m/z=230.4 [M+H]⁺.

Step E: Preparation of2-(((1r,4r)-4-((3-(2-Fluoro-3-methoxyphenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 53)

To tert-butyl 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate(36.9 mg, 0.161 mmol) in a 5 mL microwave reaction vial were added DCM(1.0 mL) and TEA (0.045 mL, 0.322 mmol). The solution was stirredbriefly and 2-fluoro-3-methoxyphenyl(phenyl)carbamic chloride (30.0 mg,0.107 mmol) was added. The reaction mixture was heated under microwaveirradiation at 80° C. and stirred for 2 h. After removal of the solventthe residue was treated with 1.0 M LiOH (2.145 mL, 2.145 mmol) and thesolution was stirred overnight at room temperature. The reaction mixturewas acidified to pH 4 by dropwise addition of 1 M HCl and extracted withethyl acetate. After evaporation of the ethyl acetate, the residue waspurified by preparative LCMS to provide the title compound as a whitesolid (22.8 mg). LCMS m/z=445.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.79-1.02 (m, 4H), 1.35-1.54 (m, 2H), 1.66-1.81 (m, 4H), 2.93 (t, J=6.00Hz, 2H), 3.28 (d, J=6.32 Hz, 2H), 3.75 (s, 3H), 3.98 (s, 2H), 6.18 (t,J=5.75 Hz, 1H), 7.02-7.07 (m, 1H), 7.08-7.18 (m, 4H), 7.21-7.27 (m, 1H),7.33 (t, J=7.83 Hz, 2H).

Example 1.98: Preparation of2-(((1r,4r)-4-((3-(4-Chloro-3-fluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 52)

From ethyl 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate and4-chloro-3-fluorophenyl(phenyl)carbamic chloride, using a similar methodto the one described in Example 1.97, Step E, the title compound wasobtained as a white solid. LCMS m/z=449.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.76-0.99 (m, 4H), 1.35-1.54 (m, 2H), 1.66-1.81 (m, 4H),2.93 (t, J=6.25 Hz, 2H), 3.27 (d, J=6.32 Hz, 2H), 3.98 (s, 2H), 6.24 (t,J=5.68 Hz, 1H), 6.91 (dd, J=9.98, 1.26 Hz, 1H), 7.21-7.35 (m, 4H),7.40-7.56 (m, 3H).

Example 1.99: Preparation of2-(((1r,4r)-4-((3-(3,4-Difluorophenyl)-3-phenylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 54)

From ethyl 2-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)acetate and3,4-difluorophenyl(phenyl)carbamic chloride, using a similar method tothe one described in Example 1.97, Step E, the title compound wasobtained as a white solid. LCMS m=433.4 [M+H]⁺; ¹H NMR (400 MHz;DMSO-d₆) δ ppm 0.76-098 (m, 4H), 1.35-1.53 (m, 2H), 1.64-1.80 (m, 4H),2.92 (t, J=6.13 Hz, 2H), 3.28 (d, J=6.44 Hz, 2H), 3.98 (s, 2H), 6.12 (t,J=5.68 Hz, 1H), 6.96 (d, J=4.17 Hz., 1H), 7.20-7.37 (m, 4H), 7.38-7.45(m, 3H).

Example 1.100: Preparation of2-(((1r,4r)-4-((Benzhydryl(methyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 86)

To ten-butyl 2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (15mg, 0.058 mmol) in DCM (0.5 mL) was added bis(2,5-dioxopyrrolidin-1-yl)carbonate (15.62 mg, 0.061 mmol) followed by TEA (0.016 mL, 0.116 mmol).The suspension was heated until the solution turned clear. The reactionwas then stirred for 2 h at room temperature, followed by 2 h at 80° C.N-methyl-1,1-diphenylmethanamine (17.18 mg, 0.087 mmol) and TEA (0.016mL, 0.116 mmol) were added to the reaction mixture and the resultingsolution was heated under microwave irradiation at 60° C. for 2 h. Theorganic solvent was evaporated and the residue was purified bypreparative LCMS to provide an intermediate which was treated with 4.0 MHCl in dioxane for 1 h at 60° C. The acid solution was evaporated andthe residue was purified by preparative LCMS to provide the titlecompound as an oil (1.0 mg). LCMS m/z=426.3 [M+H]⁺.

Example 1.101: Preparation of2-(((1r,4r)-4-((3-Benzhydryl-1,3-dimethylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 87) Step A: Preparation of1-Benzhydryl-3-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)-1,3-dimethylurea

A solution of ((1r,4r)-4-((methylamino)methyl)cyclohexyl)methanol (40.7mg, 0.259 mmol) in DCM (0.5 mL) was treated with TEA (0.090 mL, 0.647mmol) and benzhydryl(methyl)carbamic chloride (56 mg, 0.216 mmol). Thereaction was heated under microwave irradiation at 80° C. for 2 h. Thereaction mixture was concentrated and the residue was purified bypreparative LCMS to provide the title compound as an oil (26 mg). LCMSm/z=381.2 [M+H]⁺.

Step B: Preparation of2-(((1r,4r)-4-((3-Benzhydryl-1,3-dimethylureido)methyl)cyclohexyl)methoxy)aceticAcid (Compound 87)

To1-benzhydryl-3-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl)-1,3-dimethylurea(26 mg, 0.068 mmol) and rhodium(II) acetate (6.04 mg, 0.014 mmol) indichloromethane (2.0 mL) was added dropwise a solution of ethyl2-diazoacetate (9.36 mg, 0.082 mmol) in DCM (2 mL). The reaction wasstirred at room temperature for 4 days. The mixture was diluted withDCM, washed with water (five times), 1 M HCl (twice), saturated NaHCO₃(twice); and brine (twice). The combined organic layers were dried overMgSO₄ and concentrated. To the residue was added 1.0 M LiOH (2 mL), andthe mixture was stirred at 65° C. for 2 h and acidified to pH 4 with 1.0M HCl. The mixture was extracted into ethyl acetate which wassubsequently evaporated and the residue was purified by preparative LCMSto provide the title compound as an oil (1.0 mg). LCMS m z=439.6 [M+H]⁺.

Example 1.102: Preparation of2-(((1r,4r)-4-((Benzhydryl(propyl)carbamoyloxy)tnethyl)cyclohexyl)methoxy)aceticAcid (Compound 96)

To tert-butyl 2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate(200 mg, 0.774 mmol) in DCM (2.0 mL) were addedbis(2,5-dioxopyrrolidin-1-yl) carbonate (397 mg, 1.548 mmol) and TEA(0.324 mL, 2.322 mmol). The reaction was heated under microwaveirradiation at 80° C. for 2 h. N-Benzhydrylpropan-1-amine (174 mg, 0.774mmol) was added and the resulting solution was again heated undermicrowave irradiation at 60° C. for 1 h. The reaction mixture wasconcentrated and the residue was purified by flash column chromatographyto provide 210 mg of the t-butyl ester intermediate, 102 mg of which wastreated with HCl (4.0 M in dioxane, 1.161 mL, 4.64 mmol) for 3 h at roomtemperature. The reaction mixture was concentrated and the resultingresidue was purified by preparative LCMS to provide the title compoundas an oil (17.8 mg). LCMS m/z=454.4 [M+H]⁺; ¹H NMR (400 MHz; DMSO-d₆) δppm 0.54 (t, J=7.39 Hz, 3H), 0.82-1.05 (m, 6H), 1.44 (bs, 2H), 1.56-1.78(m, 4H), 3.17 (t, J=7.96 Hz, 2H), 3.26 (d, J=6.32 Hz, 2H), 3.87 (d,J=5.81 Hz, 2H), 3.97 (s, 2H), 6.43 (bs, 1H), 7.18 (d, J=7.20 Hz, 4H),7.29-7.43 (m, 6H).

Example 1.103: Preparation of Sodium2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateStep A: Preparation of 3-Fluoro-N-phenylaniline

In a 3 liter, three-neck flask equipped with mechanical stirring, asolution of 3-fluoroaniline (75 g, 675 mol), bromobenzene (73 mL, 690mol), and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(I)dichloromethane adduct (15 g, 18 mmol) in anhydrous toluene (1.3 L)containing sodium tert-butoxide (130 g, 1.35 mol) was heated at 105° C.for 3 h. The reaction mixture was then cooled to 80° C., and thenquenched by gradually pouring the reaction mixture into ice water (1 L).The aqueous layer was removed, and was then extracted with an additionalvolume of toluene (300 mL). The organic extracts were combined, rinsedwith brine, dried over MgSO₄, and passed through a silica plug (1.3 kg),eluting with toluene. The solvent was removed to give a dark amber oil(86 g). LCMS m/z (%)=188.0 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 6.45 (t,J=8.5 Hz, 1H), 6.62-6.66 (m, 2H), 6.87 (t, J=7.2 Hz, 1H), 6.98 (d, J=7.6Hz, 2H), 7.05 (q, J=7.5 Hz, 1H), 7.17 (t, J=8.6 Hz, 2H).

Step B: Preparation of 3-Fluorophenyl(phenyl)carbamic Chloride

A 3 liter three-neck mechanically stirred flask under N₂ containing asolution of 3-fluoro-N-phenylaniline (86 g, 460 mmol) in 1.2 Ldichloromethane was cooled in an ice bath to 0° C., and then triphosgene(150 g, 505 mmol) was added. A solution of pyridine (52 mL, 640 mmol) indichloromethane (200 mL) was added in a dropwise fashion. Initialaddition resulted in a temperature spike to 25° C. after the first 10 mLhad been added over 10 min. The addition was paused, and the reactionmixture was stirred for 1 h while cooling to 5° C. Addition of thepyridine solution was again commenced at a rate of 5 mL/min, at which areaction temperature of 5-10° C. was maintained. After addition wascomplete (about 1 h), the reaction had proceeded to completion, and wasquenched by the slow addition of ice water (500 g). Gas formation fromthe quench was controlled by adjusting the stirring speed, asdecomposition was largely a function of the mixing of the two immisciblelayers. Gas effluent was passed through a 20% sodium hydroxide trap,until all gas evolution had ceased (about 3 h). The aqueous layer wasremoved, and was then extracted with an additional 300 mL ofdichloromethane. The organic extracts were combined, dried over MgSO₄,and the solvent was removed. Clean product was readily isolated as aviscous, pink oil, which gradually formed a pale pink solid upon seedingwith crystals. LCMS m/z (%)=250.0 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ7.00-7.07 (m, 1H), 7.10 (d, J=9.6 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.35(d, J=7.7 Hz, 2H), 7.35-7.41 (m, 2H), 7.42-7.48 (m, 2H).

Step C: Preparation of4-(Dimethylamino)-1-((3-fluorophenyl)(phenyl)carbamoyl)pyridiniumChloride

To a solution of 3-fluorophenyl(phenyl)carbamic chloride (62.4 g, 250mmol) in acetonitrile (500 mL) in a 2 liter mechanically stirredthree-neck flask was added a solution of 4-dimethylaminopyridine (30.5g, 250 mmol) in 500 mL acetonitrile. The flask warmed slightly ascrystallization began to occur, and then cooled again to ambienttemperature. The resulting suspension was stirred overnight, cooled to10° C. in an ice bath and filtered, rinsing with cold acetonitrile (100mL) to provide the title compound as a fine, white solid (88.27 g). LCMSm/z=336.4 [M+H]⁺; ¹H NMR (400 MHz, Methanol-d₆) δ 3.29 (s, 6H), 6.92 (d,J=8.1 Hz, 2H), 7.11 (t, J=8.6 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.21 (d,J=9.5 Hz, 1H), 7.33-7.38 (m, 3H), 7.41-7.47 (m, 3H), 8.37 (d, J=8.1 Hz,2H).

Step D: Preparation of((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl-3-fluorophenyl(phenyl)carbamate

A suspension of4-(dimethylamino)-1-((3-fluorophenyl)(phenyl)carbamoyl)pyridiniumchloride (88.25 g, 237 mmol), (1r,4r)-cyclohexane-1,4-diyldimethanol(137 g, 950 mmol) and 4 dimethylaminopyridine (29.0 g, 237 mmol) inacetonitrile (1 L) was heated at 53° C. for 18 h. Upon cooling, thesolvent was removed, and the residue was taken up in isopropyl acetate(500 mL) and 1 N HCl (500 mL), heated to suspend all solids, and thenfiltered through glass fiber filter paper to remove the insolublebis-carbamate impurity. The aqueous filtrate was discarded, and theorganic filtrate was washed with an additional 500 mL of 1 N HCl,followed by water (5×500 mL). Heptane (100 mL) was added to the organicphase, which was further washed with water (2×500 mL) and brine (100mL), dried over MgSO₄, and concentrated to dryness. The residue wastaken up in isopropyl acetate (100 mL) and heptane (300 mL) was added.Crystals gradually formed over 1 h, forming a white precipitate, whichwas collected by filtration, rinsing with 25% isopropyl acetate/heptane(100 mL). The filtrate was concentrated to dryness, and the hot residuewas taken up in 25% isopropyl acetate/heptane (100 mL) and filtered hot.As the filtrate cooled, more solids precipitated, which were collectedby filtration and combined with the first crop. This material stillcontained about 5% bis-carbamate by-product, which could not be readilyremoved by filtration. The solid was then taken up in dichloromethane(200 mL) and subjected to plug filtration over 1.6 kg of silica gel,eluting the remaining bis-carbamate with dichloromethane and the productwith 20% ethyl acetate/dichloromethane to provide the title compound asa white solid (71 g). LCMS m/z=358.2 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz) δ0.91-0.98 (m, 4H), 1.35-1.44 (m, 1H), 1.54-1.60 (m, 1H), 1.68-1.73 (m,2H), 1.79-1.83 (m, 2H), 3.45 (d, J=6.4 Hz; 2H), 4.01 (d, J=6.4 Hz; 2H),6.91 (t, J=7.6 Hz, 1H), 7.04 (d, J=8.6 Hz, 2H), 7.22-7.30 (m, 4H), 7.38(t, J=7.8 Hz, 2H).

Step E: Preparation of Ethyl-2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate

In a 250 mL three-neck reactor equipped with a stirrer, a thermocouple,a cooling bath, an addition funnel and a nitrogen inlet was placed((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl-3-fluorophenyl(phenyl)carbamate(8 g, 22.38 mmol). This was dissolved in dichloromethane (150 mL). Themixture was cooled and stirred well at 4° C. in an isopropanol/ice bath.Diacetoxyrhodium (0.5 g, 1.12 mmol) was added. After the addition wascomplete, ethyl diazoacetate (3.69 g, 32.34 mmol) was dissolved indichloromethane (30 mL) and added to the reaction mixture keeping thetemperature below 10° C. After addition, the reaction mixture was warmedto 30° C. and the progress of the reaction was followed by LCMS. Basedon the LCMS ethyl diazoacetate (0.63 g, 5.52 mmol) was added, followedby more ethyl diazoacetate (0.710 g, 6.22 mmol) dissolved indichloromethane (15 mL) separately at 25° C. The reaction mixture wasstirred at 30° C. until LCMS showed complete consumption of the startingmaterial. The reaction mixture was diluted with water (100 mL) and themixture was filtered through a bed of celite (35 g) to remove thecatalyst. The organic layer was then separated and dried over magnesiumsulfate (15 g) and filtered. The solvent was removed to provide thetitle compound as an oil (9.9 g), which still contained a small amountof ethyl diazoacetate and was used without further purification. LCMSm/z=444.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.82-0.96 (m, 4H),1.22 (t, J=7.07 Hz; 3H), 1.27 (t, J=7.14 Hz, 1H), 1.37-1.53 (m, 2H),1.57-1.78 (m, 4H), 3.26 (d, J=6.32 Hz, 2H), 3.94 (d, J=6.06 Hz, 2H),4.06 (s, 2H), 4.14 (q, J=7.07 Hz, 3H), 4.23 (q, J=7.07 Hz, 1H),7.05-7.11 (m, 2H), 7.24 (dt, J=10.64, 2.26 Hz, 1H), 7.28-7.35 (m, 3H),7.36-7.45 (m, 3H).

Step F: Preparation of 2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic Acid

In a 500 mL, three-neck reactor equipped with a stirrer, a thermocouple,a heating oil bath, an addition funnel and a nitrogen inlet was placedethyl-2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate (9.9 g, 22.32mmol), which was dissolved in acetonitrile (150 mL). To this mixturelithium bromide (19.58 g, 225.00 mmol) was added. After the addition wascomplete, triethylamine (6.84 g, 67.6 mmol) was added and the reactionmixture was heated at 70° C. The progress of the reaction was followedby LCMS. Based on the LCMS the starting material was consumed in 2 h.Solvent was removed and the reaction mixture was diluted with water (200mL) and made acidic with hydrochloric acid (3 M, 7.8 mL). Theprecipitated solids were filtered and the wet solid was dissolved inisopropyl acetate (200 mL). Isopropyl acetate layer was dried overmagnesium sulfate (15 g), filtered and the solvent was removed. Theresidue was dried in a vacuum oven to provide the title compound (9.2g). LCMS m/z=416.4 [M+H]⁺; ¹H NMR (400 MHz. DMSO-d₆) δ ppm 0.81-0.96 (m,4H), 1.36-1.53 (m, 2H), 1.55-1.77 (m, 4H), 3.25 (d, J=6.44 Hz; 2H), 3.93(d, J=5.94 Hz, 2H), 3.97 (s, 2H), 7.05-7.13 (m, 2H), 7.24 (dt, J=10.64,2.26 Hz, 1H), 7.28-7.36 (m, 3H), 7.37-7.46 (m, 3H), 12.53 (bs, 1H)

Step G: Preparation of 2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic Acid Sodium Salt

In a 500 mL, three-neck reactor equipped with a stirrer, a thermocouple,a heating oil bath, an addition funnel and a nitrogen inlet was placed2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (9.2 g, 22.83mmol) and 2-propanol (100 mL). The reaction mixture was heated at 30° C.(bath temperature), until all of the acid was dissolved completely. Tothe orange solution, sodium hydroxide (1 M, 22 mL, 22 mmol) was addedslowly keeping the temperature around 25° C. The sodium salt separatedout as crystals. The thick slurry was stirred at 25° C. for 2 h and thencooled in an ice water bath for 40 min. The solids were filtered anddried in a vacuum oven at 40° C. overnight until most of the residual2-propanol was removed to provide the title compound (7.4 g). LCMS mz=416.5 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77-0.95 (m, 4H),1.34-1.53 (m, 2H), 1.55-1.75 (m, 4H), 3.19 (d, J=6.44 Hz, 2H), 3.52 (s,2H), 3.93 (d, J=5.94 Hz, 2H), 7.05-7.13 (m, 2H), 7.24 (dt, J=10.64, 2.26Hz, 1H), 7.28-7.35 (m, 3H), 7.37-7.46 (m, 3H).

Example 1.104: Preparation of Sodium2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate

To 5.0 g of ((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl3-fluorophenyl(phenyl)carbamate was added toluene (30 mL), 50% NaOH (28mL), tetrabutylammonium bromide (2.3 g) and tert-butyl bromoacetate(10.3 mL). The reaction mixture was stirred at room temperature forabout 7 h and monitored by LC-MS to give tert-butyl2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methayy)acetate.The mixture was then heated at 50-60° C. for about 4 hours and monitoredby LC-MS to give2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid (Compound 23). The mixture was then acidified with 12 N HCl and thephases separated. The organic layer was concentrated and the residuesuspended in isopropyl alcohol (20 mL). Thereafter, 50% sodium hydroxide(˜1 mL) and water (4 mL) were added at 50-60° C. The mixture was stirredat 40-50° C. for 1 h and then cooled to room temperature. The mixturewas filtered and washed with isopropyl alcohol (10 mL). The solid wasdried under reduced pressure at 50° C. to leave the title compound (4.0g, 66%). LCMS m/z=416.5 [M-Na+H]⁺.

Example 1.105: Preparation of 4-Chloro-N-phenylaniline

Method 1.

A solution of 4-chloroaniline (25.5 g, 200 mmol), bromobenzene (31.4 g,200 mmol), and dichloro[1,1bis(diphenylphosphino)ferrocene]palladium(11) dichloromethane adduct(4.9 g, 6.0 mmol) in anhydrous toluene (500 mL) containing sodiumtert-butoxide (38.4 g, 400 mmol) was refluxed under N₂ for 90 min. Thereaction mixture was cooled until it began to solidify, and then water(400 mL) was added, and the aqueous layer was removed. The organic layerwas rinsed with brine, dried over MgSO₄, and passed through a silicaplug, eluting with toluene. The solvent was removed to give a palereddish amber solid (35.3 g). LCMS m/z=204.4 [M+H]⁺; ¹H NMR (400 MHzCDCl₃) δ ppm 7.00 (t, J=7.6 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 7.10 (d,J=7.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 7.31 (t, J=7.7 Hz, 2H).

Method 2.

A solution of 4-bromochlorobenzene (38.3 g, 200 mmol), aniline (18.6 g,200 mmd), and dichloro[1,1 bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (4.9 g, 6.0 mmol) in anhydrous toluene (500 mL)containing sodium tert-butoxide (38.4 g, 400 mmd) was refluxed under N₂for 90 min. The reaction mixture was cooled until it began to solidify,and then water (400 mL) was added, and the aqueous layer was removed.The organic layer was rinsed with brine, dried over MgSO₄, and passedthrough a silica plug, eluting with toluene. The solvent was removed togive a reddish amber solid (37.2 g). LCMS m/z=204.4 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ ppm 7.00 (t, J=7.6 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 7.10(d, J=7.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 7.31 (t, J=7.7 Hz, 2H).

Example 1.106: Preparation of Sodium2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate

Method 1.

Step A: Preparation of ((1r,4r)-4 (hydroxymethyl)cyclohexyl)methyl 4chlorophenyl(phenyl)carbamate

4-Chloro-N-phenylaniline (15.0 g, 73.6 mmol), tribasic potassiumphosphate. (fine powder, 4.69 g, 22.1 mmol), N,N′-carbonyldiimidazole(13.14 g, 81 mmol) and acetonitrile (75 mL) were charged to a 500-mL,jacketed, four-necked cylindrical reaction flask equipped with amechanical stirrer and a condenser. The reaction mixture was heated at65° C. under nitrogen and monitored by HPLC. After about 2.5 h HPLCshowed >98% conversion to the intermediateN-(4-chlorophenyl)-N-phenyl-1H-imidazole-1-carboxamide. After about 5.5h a solution of (1r,4r)-cyclohexane-1,4-diyldimethanol (37.2 g, 258mmol) in acetonitrile (150 mL) at 65° C. was added to the reactionmixture over 20 min. The resulting mixture was heated at 65° C.overnight. HPLC showed about 98% conversion to the required product. Themixture was filtered, and the cake was rinsed with acetonitrile (2×25mL). The filtrate was concentrated under reduced pressure (40° C., 32torr) 124.125 g of distillate was collected. The residue was dilutedwith water (50 mL) and this mixture was concentrated under reducedpressure (40° C., 32 torr) and 35.184 g of distillate was collected. Theresidue was diluted with water (50 mL) and the resulting mixture wasallowed to stir overnight to give a white paste. The mixture wasfiltered, and the cake was rinsed with 25% acetonitrile/water (2×75 mL).The solid was dried in a vacuum oven to leave a white solid (22.271 g);94.8% purity by HPLC peak area. LCMS m/z=374.3 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.77-0.93 (m, 4H) 1.23 (dd, J=6.22, 3.51 Hz, 1H) 1.47(dd, J=6.32, 2.91 Hz, 1H) 1.56-1.76 (m, 4H) 3.20 (t, J=5.78 Hz, 2H) 3.92(d, J=6.13 Hz, 2H) 4.33 (t, J=5.31 Hz, 1H) 7.28-7.35 (m, 5H) 7.38-7.47(m, 4H).

Step B: Preparation of Sodium2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloryknethyl)cyclohexyl)methoxy)acetate

In a 1 L 3-neck flask fitted with an overhead stirrer was placed((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl4-chlorophenyl(phenyl)carbamate (30 g), TBAB (7.8 g) and toluene (180mL) and the mixture stirred at room temperature. To this mixture wasadded 50% NaOH (180 mL) followed by addition of tert-butyl bromoacetate(17.8 mL). The mixture was stirred at room temperature for 7 h. Themixture was then heated at 50-60° C. for 4 h. The mixture was thenneutralized with concentrated HCl (300 mL). The mixture was filtered andthe resulting filtrate was separated into two phases. The aqueous layerwas extracted with toluene (80 mL). The combined organic layers werewashed with water and the solvent was evaporated. The residue wasazeotroped with isopropyl alcohol (150 mL) to remove the remainingtoluene. Isopropyl alcohol (150 mL) was added to dissolve the residueand to this solution was added 12.5% NaOH solution (17 mL) to give a pHof 7-8. The resulting precipitate was collected by filtration and thefilter cake was dissolved in water/acetone (280 mL; 1:1) at 55-60° C.The solution was filtered and the filtrate was diluted with acetone (320mL) and stirred at room temperature overnight. The resulting slurry wascooled to 0-5° C. and then filtered. The filter cake was suspended inacetonitrile (440 mL), stirred at room temperature for 16 h and thenfiltered. The filter cake was dried at 60-70° C. under reduce pressureto leave the desired product (21.1 g); >99% purity by HPLC peak area.LCMS m/z=432.3 [M-Na+H]⁺.

Method 2.

Step A: Preparation of ((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl4-chlorophenyl(phenyl)carbamate

A 50-liter glass-lined reactor equipped with overhead agitation, jackettemperature control, and a nitrogen atmosphere was charged with(1r,4r)-cyclohexane-1,4-diyldimethanol (3.97 kg) and acetonitrile (12.71kg). The reactor contents were stirred at 130 rpm and heated to 63° C.for 1.2 h to achieve dissolution. The mixture was cooled to <40° C. andthen filtered. The filtrate was stored in a carboy,4-Chloro-N-phenylaniline (1.60 kg), K₃PO₄ (0.50 kg), CDI (1.41 kg) andacetonitrile (6.29 kg) were charged to a 50-liter glass-lined reactorequipped with overhead agitation, jacket temperature control, and anitrogen atmosphere. The reactor contents were stirred at 130 rpm andheated to 65° C. to 70° C. for 3 h, after which conversion of4-chloro-N-phenylaniline toN-(4-chlorophenyl)-N-phenyl-1H-imidazole-1-carboxamide was 98.0% by HPLCpeak area. The reaction mixture was cooled to less than 40° C. and thesolution of (1r,4r)-cyclohexane-1,4-diyldimethanol in acetonitrileprepared earlier was added to the mixture. The reactor contents werestirred at 130 rpm and heated at 65 to 70° C. for 19 h, after whichconversion of N-(4-chlorophenyl)-N-phenyl-1H-imidazole-1-carboxamide to((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl4-chlorophenyl(phenyl)carbamate was verified to be 98.0% by HPLC peakarea. The reactor contents were filtered and the filter cake was rinsedwith acetonitrile (2.00 kg). The filtrate was transferred back to thereactor and most of the acetonitrile (18.48 kg) was then removed at 22°C. by vacuum distillation at 80 mm Hg. Water (5.34 kg) was added to thereactor and 1.55 kg of water/acetonitrile mixture was then removed byvacuum distillation at 29° C. and 70 mm Hg. Water (5.34 kg) was added tothe reactor and the product precipitated during the addition. Theresulting mixture was stirred at 20° C. to 25° C. for 13 h. Theprecipitated product was filtered and washed with aqueous acetonitrilein two portions (1.59 kg acetonitrile dissolved in 6.00 kg water). Theproduct was dried under reduced pressure at ≤ 60° C. (untilloss-on-drying was ≤ 2 wt %) to give the title compound as an off-whilesolid (2.29 kg, 78% yield; 97% purity by HPLC peak area.)

Step B: Preparation of Sodium2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate

((1r,4r)-4-(Hydroxymethyl)cyclohexyl)methyl4-chlorophenyl(phenyl)carbamate (1.70 kg), tetrabutylammonium bromide(0.44 kg) and toluene (7.36 kg) were charged to a 50-liter glass-linedreactor equipped with overhead agitation, jacket temperature control,and a nitrogen atmosphere. The mixture was stirred for 1 h at 20° C. Tothe resulting solution was added 50 wt % aqueous sodium hydroxide (15.34kg) and the jacket temperature was set to 10° C. Then tert-butylbromoacetate (1.33 kg) was added sufficiently slowly to maintain thestirred reaction mixture at 5-15° C. with reactor jacket cooling. Themixture was stirred at 5-15° C. for 8.1 h. Conversion of((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl4-chlorophenyl(phenyl)carbamate to tert-butyl2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatewas >90.0% by HPLC peak area. The reactor contents were heated at 50-60°C. for 7.2 h. Conversion of tert-butyl(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateto2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid was >90.0% by HPLC peak area. The reactor contents were then cooledto 15° C. and concentrated hydrochloric acid (18.87 kg) was added to themixture at a rate sufficiently slow to maintain an internal temperature<50° C. The mixture was filtered to remove the solid sodium chloridefrom the reactor. The filtrate separated into two phases and the organicphase was removed. The aqueous layer was extracted with toluene (4.55kg). The organic phases were combined and the mixture was distilled at30° C. and 40 mm Hg to remove most of the toluene. Then, IPA (6.75 kg)was charged to the reactor and the resulting solution was distilled at28° C. and 40 mm Hg to remove solvent (5.05 Kg). IPA (6.68 kg) wascharged a second time to the reactor and the resulting mixture wasvacuum distilled at 37° C. and 40 mm Hg to remove solvent (4.98 kg).Then, IPA (6.77 kg) was charged to the reactor for the third time andthe reactor contents were heated to 40° C. Sodium hydroxide (12.5%,0.87kg) was added to the reactor. The resulting mixture had a pH of 7. Themixture was agitated at 155 rpm for 2 h at 40° C. The productprecipitated, and the solid was filtered. The filter cake was washedwith IPA (3.01 kg). The filter cake was transferred to a reactor usingacetone (6.27 kg) and water (7.95 kg) and the mixture was heated at 59°C. for 3 h. The resulting mixture was filtered through a sintered glassfilter and the filtrate was transferred to a reactor. Acetone (15.82 kg)was added and the mixture stirred for 66 h at 20° C. The reactorcontents were further stirred at 0° C. for 2 hours, filtered and thefilter cake was washed with acetone (3.2 kg). The filter cake was thentransferred back to the reactor with the aid of acetonitrile (17.79 kg).The reactor contents were stirred at 100 rpm and 20° C. for 18.5 h. Theslurry was filtered and the cake was washed with two portions ofacetonitrile (10.26 kg total). The solid was dried at 65° C. to 70° C.under reduced pressure for 27 h, and then sieved through a 1.18 mm meshscreen. The product was further dried under reduced pressure at ≤70° C.to an acetonitrile level of 2000 ppm, to leave the title compound as awhite to off-white solid (0.65 kg, 32% yield; 98.8% purity by HPLC peakarea.)

Example 1.107: Preparation of Sodium2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxyknethyl)cyclohexyl)methoxy)acetateHydrate

Sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatewas slurried in water for 3 days at 40° C., and then filtered to givethe title compound as a solid. The TGA thermogram of the title compound(FIG. 12 ) shows a weight loss of about 13%, indicating that thecompound is a hydrate. The PXRD pattern for the hydrate is shown in FIG.13 .

Example 1.108: Preparation of Sodium2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateHydrate

Crude sodium2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate(0.422 g) was suspended in water (10 volumes) and heated to 85° C.(bath). The sodium2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoloxy)methyl)cyclohexyl)methoxy)acetatedid not dissolve. Ethanol (8.5 volume) was added and a solution formed.The solution was hot-filtered, the solvate crystallized, and thesuspension was stirred at room temperature for 1 h and filtered. Thesolids were dried in vacuum oven at 45° C. overnight. The TGA thermogramof the title compound (FIG. 14 ) shows a weight loss of about 4.3%,indicating that the compound is a mono-hydrate. The PXRD pattern isshown in FIG. 15 .

Example 1.109: Preparation of Magnesium2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateSolvate

Mg(OAc)₂ (aqueous solution, 2.13 M) was added to a solution of2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid in IPA (64.456 mg/mL) at room temperature to achieve a 1:2 ratio ofmagnesium to2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid. No precipitation occurred so the solution was allowed to evaporateto dryness to produce a crystalline solid. The TGA thermogram of thetitle compound (FIG. 16 ) shows a weight loss of about 18.9%, indicatingthat the compound is a solvate. The PXRD pattern for the solvate isshown in FIG. 17 .

Example 1.110: Preparation of Potassium 2-(((1r,4r)-4(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateSolvate

Potassium carbonate (aqueous solution, 2.19M) was added to a solution of2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid in IPA (64.456 mg/mL) at room temperature to achieve a 1:1 ratio ofpotassium to2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid. A precipitate formed after −15 min and the solid was isolated byfiltration. The TGA thermogram of the title compound (FIG. 18 ) showsweight losses of about 2.0% below about 93° C. and about a further 3.8%below about 177° C., indicating that the compound is a solvate. The PXRDpattern for the solvate is shown in FIG. 19 .

Example 1.111: Preparation of Calcium2-(((1r,4r)-4-(((3-Fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateSolvate

Ca(OAc)₂ (aqueous solution, 2.13M) was added to a solution of2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid in IPA (64.456 mg/mL) at room temperature to achieve a 1:2 ratio ofcalcium to2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid. A white precipitate formed immediately. The solid was isolated byfiltration. The TGA thermogram of the title compound (FIG. 20 ) shows aweight loss of about 8.2%, indicating that the compound is a solvate.The PXRD pattern for the solvate is shown in FIG. 21 .

Example 1.112: Preparation of 2-(2-(((1r,4r)-4.(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetamido)ethanesulfonicAcid (Compound 99)

Method 1.

2-(((1r,4r)-4-(((4-Chlorophenyl)phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (0.30 g, 0.695 mmol) was dissolved in SOCl₂ (5.0 mL,68.5 mmol) (bubbling was observed). The reaction was heated to refluxand stirred for 2 h, and then concentrated and dried overnight underreduced pressure. The resulting((1r,4r)-4-((2-chloro-2-oxoethoxy)methyl)cyclohexyl)methyl4-chlorophenyl(phenyl)carbamate was dissolved in THE (2 mL) with gentleheating. To this was added a solution of 2-aminoethanesulfonic acid(0.113 g, 0.903 mmol) and sodium hydroxide (0.038 g, 0.938 mmol) inwater (0.6 mL). The reaction was vigorously stirred at room temperaturefor 1 h. The solvent was removed under reduced pressure and the residuewas dissolved in DMSO (3 mL) and filtered. The filtrate was purified byHPLC to yield the title compound as a white solid (70.1 mg, 18.35%).Exact mass calculated for C₂₅H₃₁ClN₂O₇S: 538.2, found: LCMS m/z=539.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78-0.97 (m, 4H) 1.37-1.52 (m,2H) 1.52-1.62 (m, J=7.83 Hz, 2H) 1.67-1.77 (m, 2H) 2.54 (t, J=6.44 Hz,2H) 3.21 (d, J=6.32 Hz, 2H) 3.37 (q, J=5.81 Hz, 2H) 3.76 (s, 2H) 3.90(d, J=6.06 Hz, 2H) 7.22-7.34 (m, 5H) 7.35-7.48 (m, 4H) 7.91 (bs, 1H).

Method 2.

To a solution of sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate(50 mg, 0.11 mmol) in DMF (5 ml) and H2O (2.5 ml), was added1H-benzo[d][1,2,3]triazol-1-ol hydrate (16.87 mg, 0.11 mmol) followed by2-aminoethanesulfonic acid (13.79 mg, 0.11 mmol) at ambient temperature.The reaction was heated to 120° C. for 10 h. After cooling to roomtemperature, the reaction was poured into water, extracted with ethylacetate, and then dried with MgSO₄. The organic layer was concentratedunder reduced pressure and the resulting residue was purified by HPLC toafford the title compound as a white solid (12 mg). Exact masscalculated for C₂₅H₃₁ClN₂O₇S: 538.2, found: LCMS m/z=539.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.73-1.85 (m, 4H), 1.35-1.41 (m, 2H),1.50-1.52 (m, 2H), 1.65-1.69 (m, 2H), 2.50 (m, 2H), 3.15 (d, J=6.4 Hz,2H), 3.36 (m, 2H), 3.72 (s, 2H), 3.89 (d, J=6.2 Hz, 2H), 7.12-7.25 (m,5H), 7.27-7.49 (m, 4H), 7.85 (br, 1H).

Example 1.113: Preparation of2-(2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetanrido)aceticAcid (Compound 100)

2-(((1r,4r)-4-(((4-Chlorophenyl phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (0.30 g, 0.695 mmol) was dissolved in SOCl₂ (5.0 mL,68.5 mmol) (bubbling was observed). The reaction was heated to refluxand stirred for 2 h, and then concentrated and dried overnight underreduced pressure. The resulting((1r,4r)-4-((2-chloro-2-oxoethoxy)methyl)cyclohexyl)methyl4-chlorophenyl(phenyl)carbamate was dissolved in 11-IF (2 mL) withgentle heating. To the resulting solution was added a solution ofglycine (0.052 g, 0.688 mmol) and sodium hydroxide (0.030 g, 0.757 mmol)in water (0.6 mL). The reaction was vigorously stirred at roomtemperature for 1 h. The solvent was removed under reduced pressure andthe residue was dissolved in DMSO (3 mL) and filtered. The filtrate waspurified by HPLC to yield the title compound as a white solid (20.0 mg,5.88%). Exact mass calculated for C₂₅H₂₉ClN₂O₆: 488.2, found: LCMSm/z=489.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.97 (m, 4H)1.40-1.53 (m, 2H) 1.55-1.63 (m, 2H) 1.69-1.80 (m, 2H) 3.25 (d, J=6.57Hz, 2H) 3.78 (d, J=6.06 Hz, 2H) 3.84 (s, 2H) 3.90 (d, J=6.06 Hz, 2H)7.22-7.33 (m, 5H) 7.34-7.46 (m, 4H) 7.80 (bs, J=5.81, 5.81 Hz, 1H).

Example 1.114: Preparation of2-(((1r,4r)-4-(((4-Chlorophenyl)(4-hydroxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 98) Step A: Preparation oftert-Butyl(4-iodophenoxy)dimethylsilane

4-Iodophenol (1.0 g, 4.55 mmol) was dissolved in dichloromethane (5 mL),tert-Butyldimethylsilyl chloride (0.685 g, 4.55 mmol) and imidazole(0.309 g, 4.55 mmol) were added. The reaction was stirred overnight atroom temperature. The reaction mixture was partitioned between water (30mL) and dichloromethane (30 mL). The organic layer was removed and theaqueous layer was extracted with dichloromethane (30 mL). The organiclayers were combined, dried and concentrated, and the residue waspurified by chromatography (0-10% EtOAc/hexanes) to give the titlecompound as a light yellow oil (1.45 g, 94%).

Step B: Preparation of tert-Butyl2-(((1r,4r)-4-((4-chlorophenylcarbamoyloxy)methylcyclohexyl)methoxy)acetate

tert-Butyl 2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)methoxy)acetate (2.4g, 9.29 mmol) and 4-chlorophenylisocyanate (1.712 g, 11.15 mmol) weredissolved in dichloromethane (20 mL). Then, pyridine (1.503 mL, 18.58mmol) was added. The reaction was heated to reflux and stirredovernight. The solvents were removed under reduced pressure and theresidue was purified by column chromatography (0-10% EtOAc/hexanes) toyield the title compound as a light yellow solid (1.45 g, 36.4%).

Step C: Preparation of 2-(((1r,4r)-4(((4-Chlorophenyl)(4-hydroxyphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid

tert-Butyl 2-(((1r,4r)-4-((4chlorophenylcarbamoyloxy)methyl)cyclohexyl)methoxy)acetate (100 mg,0.243 mmol), tert-butyl(4-iodophenoxy)dimethylsilane (81 mg, 0.243mmol), potassium phosphate (103 mg, 0.486 mmol), copper(I) iodide (23.12mg, 0.121 mmd), and trans-1,2-diaminocyclohexane (29.2 μL, 0.243 mmol)in dioxane (1.6 mL) were heated at 150° C. for 5 h under microwaveirradiation. The reaction mixture was filtered though a plug of MgSO₄,the solvent was removed under reduced pressure, and the residue waspurified by column chromatography (0-10% EtOAc/hexanes). The purifiedmaterial was dissolved in HCl (4 M in Dioxane; 0.5 mL) and the mixturewas stirred at room temperature overnight. The solvent was removed underreduced pressure and the title compound was isolated by preparative HPLC(30-85% MeOH/H₂O, 30 min).

Example 1.115:2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticAcid (Compound 22)

In a 1 L 3-neck flask fitted with an overhead stirrer was added((1r,4r)-4-(hydroxymethyl)cyclohexyl)methyl4-chlorophenyl(phenyl)carbamate (30 g), TBAB (7.8 g) and toluene (150mL). To the resulting solution was added ten-butyl bromoacetate (17.8mL). The mixture was cooled to 5-10° C. before slowly adding 50% sodiumhydroxide (180 mL). The mixture was stirred at 3-10° C. for 7 h, allowedto sit at 18-24° C. overnight, and then heated at 45-50° C. for 4 h. Themixture was then acidified with conc. HCl (˜260 mL) to pH 2. The mixturewas filtered and the filtrate was transferred to a separatory funnel.The phases were separated and the aqueous layer extracted once againwith toluene (30 mL). The combined toluene layer was evaporated to anoil. To the oil was added 25% aqueous acetone (90 mL) and 12.5% sodiumhydroxide solution (14 mL). The resulting solid was filtered and thefilter cake was recrystallized from water (60 mL) and acetone (300 mL).The recrystallized material was suspended in water (100 mL) and 2 N HCl(30 mL) was added to pH 3. The mixture was allowed to stir overnight.The suspension was filtered and the filter cake was resuspended in water(150 mL). The mixture was stirred and filtered and the filter cake wasdried at 65° C. in a vacuum oven to give the title compound as a whitesolid (19.33 g, HPLC purity: 97.4% by weight). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.82-0.99 (m, 4H), 1.38-1.52 (m, 2H), 1.52-1.80 (m, 4H), 3.26 (d,J=3.0 Hz, 2H), 3.93 (d, J=3.0 Hz, 2H), 3.97 (s, 1H), 7.25-7.38 (m, 5H),7.39-7.50 (m, 4H), 12.51 (bs, 1H).

Example 2: Homogeneous Time-Resolved Fluorescence (HTRF®) Assay ForDirect cAMP Measurement

Compounds were screened for agonists of the human prostacyclin (PGI2)receptor using the HTRF® assay for direct cAMP measurement (Gabriel etal., ASSAY and Drug Development Technologies, 1:291-303, 2003) andrecombinant CHO-K1 cells stably transfected with human prostacyclinreceptor. CHO-K₁ cells were obtained from ATCC® (Manassas, Va.; Catalog#CCL-61). An agonist of the prostacyclin receptor was detected in HTRF®assay for direct cAMP measurement as a compound which increased cAMPconcentration. HTRF® assay also was used to determine EC₅₀ values forprostacyclin receptor agonists.

Principle of the assay: The HTRF® assay kit was purchased fromCisbio-US, Inc. (Bedford, Mass.; Catalog #62AM4PEC). The HTRF® assaysupported by the kit is a competitive immunoassay between endogenouscAMP produced by the CHO-K1 cells and tracer cAMP labeled with the dyed2. The tracer binding is visualized by a monoclonal anti-cAMP antibodylabeled with Cryptate. The specific signal (i.e., fluorescence resonanceenergy transfer. FRET) is inversely proportional to the concentration ofunlabeled cAMP in the standard or sample.

Standard curve: The fluorescence ratio (665 nm/620 nm) of the standards(0.17 to 712 nM cAMP) included in the assay was calculated and used togenerate a cAMP standard curve according to the kit manufacturer'sinstructions. The fluorescence ratio of the samples (test compound orcompound buffer) was calculated and used to deduce respective cAMPconcentrations by reference to the cAMP standard curve.

Setup of the assay: The HTRF® assay was carried out using a two-stepprotocol essentially according to the kit manufacturer's instructions,in 20 μL total volume per well in 384-well plate format (ProxiPlates;PerkinElmer. Fremont, Calif.: catalog #6008280). To each of theexperimental wells was transferred 3000 recombinant CHO-K1 cells in 5μL, assay buffer (phosphate buffered saline containing calcium chlorideand magnesium chloride (Invitrogen, Carlsbad, Calif.; catalog #14040)supplemented with IBMX (100 μM) and rolipram (10 μM) (phosphodiesteraseinhibitors; Sigma-Aldrich, St. Louis, Mo.; catalog #I5879 and catalog#R6520, respectively) and 0.1% bovine serum albumin (BSA) fraction V(Sigma-Aldrich; catalog #A3059)), followed by test compound in 5 μLassay buffer or 5 μL assay buffer. The plate was then incubated at roomtemperature for 1 h. To each well was then added 5 μL cAMP-d2 conjugatein lysis buffer and 5 μL Cryptate conjugate in lysis buffer according tothe kit manufacturer's instructions. The plate was then furtherincubated at room temperature for 111, after which the assay plate wasread.

Assay readout: The HTRF® readout was accomplished using a PHERAstar (BMGLABTECH Inc., Durham, N.C.) or EnVision™ (PerkinElmer, Fremont Calif.)microplate reader.

Certain compounds of the present invention and their correspondingactivity values are shown in TABLE B.

TABLE B human PGI2 receptor Compound No. EC₅₀ (nM) (HTRF ®) 6 61.09 3556.89 55 5.14 71 19.10

Certain other compounds of the invention had activity values rangingfrom about 2.7 nM to about 2.65 μM in this assay.

Example 3: Human Platelet Aggregation Inhibition Test

Blood collected from healthy human volunteers in aqueous trisodiumcitrate solution was centrifuged at 150 g for 15 min and the upper layerwas recovered to obtain platelet-rich plasma (PRP). The residual bloodwas centrifuged at 3000 μl g for 10 min and the supernatant wascollected as platelet-poor plasma (PPP). Platelet concentration in thePRP was determined using the Z series Beckman Coulter particle counter(Beckman, Fullerton, Calif.) and adjusted to 250,000 platelets/μL usingPPP. 480 μL of PRP was pre-incubated at 37° C. and stirred at 1200 rpmwith 10 μL aqueous test compound solution for 1 min prior to inductionof aggregation by the addition of 10 μL of aqueous adenosine diphosphate(ADP) solution to adjust the final ADP concentration in the PRP to1×10⁻⁵ M. The maximal amplitude of aggregation response within 3 min wasdetermined and measured in triplicate using the Chronolog model 490aggregometer (Chrono-log Corp., Havertown, Pa.). Percent inhibition ofaggregation was calculated from the maximum decrease in optical densityof the control (addition of water in place of the test compoundsolution) sample and of the samples containing test compound. The testcompound was added to adjust the final concentration to the range 10⁻⁹to 10⁻⁴ M, and IC₅₀ values were determined by inhibition percentage ofaggregation at each concentration. The results are shown in Table C.

TABLE C Compound No. human PRP IC₅₀ (nM) 2 73 30 210 50 12.6 88 70

Certain other compounds of the invention had activity values rangingfrom about 10.5 nM to about 1.59 μM in this assay.

It is apparent that the compounds of the present invention markedlyinhibit platelet aggregation in human PRP.

Example 4: Rat Model of Pulmonary Arterial Hypertension

Animals: Male Wistar rats (100-150 g at start of study) (Charles RiverLaboratories, Wilmington, Mass.) were housed two per cage and maintainedin a humidity—(40-60%) and temperature—(68-72° F.) controlled facilityon a 12 hr:12 hr light/dark cycle (lights on at 6:30 am) with freeaccess to food (Harlan Teklad, Orange Calif., Rodent Diet 8604) andwater. Rats were allowed one week of habituation to the animal facilitybefore testing.

Rat monocrotaline model: The rat monocrotaline (MCT) model is a standardand well-accepted model of pulmonary arterial hypertension. MCT inducesacute pulmonary endothelial damage associated with pulmonary vascularinflammation. Subsequently, pulmonary artery smooth muscle cellsproliferate, occluding small pulmonary vessels and leading to severepulmonary arterial hypertension including right ventricular hypertrophy.(See, e.g., Schernuly el al., Circ. Res., 2004, 94:1101-1108.)

Rats were randomly given a single subcutaneous injection of either 60mg/kg MCT (Sigma, St. Louis, Mo.) or 0.9% saline (sham) and assigned toreceive oral administration of 20% hydroxypropyl beta-cyclodextrin(vehicle) or test compound (30 mg/kg; FIGS. 7 and 8 ). 10-11 rats wereused per treatment group. 24 h following MCT administration, testcompound or vehicle was administered by oral gavage twice a day for 21consecutive days. Heart chamber weights were measured on Day 22. Ratswere anesthetized with intraperitoneal pentobarbital (50 mg/kg), thechest cavity was opened and the heart was excised. The right ventriclewas dissected free from the septum and left ventricle and both partswere weighed. The ratio of right ventricular (RV) weight to leftventricle plus septum (LV+S) weight (this ratio is indicated as“RV/(LV+S)” in FIGS. 7 and 8 ) was calculated as an index of thehypertrophic response to the induced pulmonary arterial hypertensionand, as such, as an index of a test compound's therapeutic efficacy forpulmonary arterial hypertension.

It is apparent from inspection of FIGS. 7 and 8 that oral administrationof Compounds 23 and 22 inhibited the hypertrophic response to theinduced pulmonary arterial hypertension and, as such, evidencedtherapeutic efficacy for pulmonary arterial hypertension.

Example 5: Powder X-Ray Diffraction

Powder X-ray Diffraction (PXRD) data were collected on an X'Pert PRO MPDpowder diffractometer (PANalytical, Inc.) with a Cu source set at 45 kVand 40 mA, a Ni-filter to remove Cu Kβ radiation, and an X'Celeratordetector. The instrument was calibrated by the vendor using a siliconpowder standard NIST #640c. The calibration was found to be correct whenit was tested with NIST #675 low-angle diffraction standard. Sampleswere prepared for PXRD scanning by placing several milligrams of as-iscompound onto a sample holder and smoothing as flat as possible bypressing weigh paper down on the sample with a flat object. The sampleswere analyzed using a spinning-sample stage. Scans covered the range of5 to 40 °2θ. A continuous scan mode was used with a step size of 0.0170°2θ. Diffraction data were viewed and analyzed with the X′Pert DataViewer Software, version 1.0a and X'Pert HighScore Software, version1.0b. The PXRD pattern for the crystalline form of sodium2-(((1r,4r)-4-(((4-chloropheml)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateis shown in FIG. 9 . The PXRD pattern for a sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatehydrate is shown in FIG. 13 . The PXRD pattern for a sodium2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatehydrate is shown in FIG. 15. The PXRD pattern for a magnesium2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatesolvate is shown in FIG. 17 . The PXRD pattern for a potassium2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatesolvate is shown in FIG. 19 . The PXRD pattern for a calcium2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatesolvate is shown in FIG. 21 .

Example 6: Differential Scanning Calorimetry

Differential Scanning Calorimetry (DSC) was performed on a TAinstruments, Inc. DSC Q1000 or Q2000 at 10° C./min. The instrument wascalibrated at this scan rate by the vendor for temperature and energyusing the melting point and enthalpy of fusion of an indium standard.Samples were prepared by taring a sample-pan lid along with a sample-panbottom on a Mettler Toldeo MX5 balance. Sample was placed in the bottomof the tared sample pan. The sample-pan lid fitted snuggle in thesample-pan bottom. The sample and pan were reweighed to get the sampleweight. Thermal events (for example, onset temperature, enthalpy offusion) are calculated using the Universal Analysis 2000 software,version 4.1D, Build 4.1.0.16. The DSC thermogram for the crystallineform of sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateis shown in FIG. 11 overlaid with the TGA trace.

Example 7: Thermal Gravimetric Analysis

Thermal Gravimetric Analysis (TGA) was performed on the TA Instruments,Inc. TGA Q500 or Q5000. The instrument is calibrated by the vendor at10° C./min. for temperature using the curie point of a ferromagneticstandard. The balance is calibrated with a standard weight. Sample isplaced into an open sample pan, previously tared on the TGA balance.Thermal events such as weight-loss are calculated using the UniversalAnalysis 2000 software, version 4.1D, Build 4.1.0.16. The TGA thermogramfor the crystalline form of sodium2-((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetateis shown in FIG. 11 overlaid with the DSC trace. The TGA thermogram fora sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatehydrate is shown in FIG. 12 . The TGA thermogram for a sodium 2-(((Ir,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatehydrate is shown in FIG. 14 . The TGA thermogram for a magnesium2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatesolvate is shown in FIG. 16 . The TGA thermogram for potassium2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatesolvate is shown in FIG. 18 . The TGA thermogram for calcium2-(((1r,4r)-4-(((3-fluorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatesolvate is shown in FIG. 20 .

Example 8: Dynamic Vapor Sorption (DVS)

Hygroscopicity was measured using a dynamic moisture-sorption analyzer,VTI Corporation, SGA-100. The sample was placed as-is in a tared sampleholder on the VTI balance. A drying step was run at 40° C. and ˜1% RHfor 60 to 120 min. The isotherm conditions are 25° C. with steps of 20%RH from 10% RH up to 90% RH and back to 10% RH. The weight was checkedevery 2 min. Percent weight change of <0.01% in 20 min or 2 h, whicheveroccurs first, is required before continuing to the next step. The DVSprofile for the crystalline form of sodium2-((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclahexyl)methoxy)acetateis shown in FIG. 10 .

Example 9: Interspecies Comparison of Hepatocyte Metabolism of Sodium2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate

All cryopreserved hepatocytes were thawed and diluted to a desired celldensity (1×10⁶ celis/mL) according to the supplier's (Xenotech)guidelines using hepatocytes isolation kit. Cell viability wasdetermined by trypan blue exclusion using a hemacytometer. A typicalincubation mixture contained human, cynomolgus monkey, beagle dog orSprague-Dawley rat hepatocytes (200,00) cells/199 AL) in designatedwells of a 48-well plate containing incubation medium (Phenol red-freeWaymouth's medium). The incubation mixture plate was incubated at 37°C., 5% CO₂, for 5 min before starting the reaction with 1 μL of sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate(Compound 22 sodium salt)(100 μM final concentration). One incubationplate was prepared for each time point (i.e., 0, 60, 120, and 240 min)with samples being prepared in duplicate. Incubations were conducted at37° C., 5% CO₂ and 100% relative humidity in an incubator. At each timepoint, one incubation plate was removed form the incubator, and reactionwas terminated by adding 400 μL of acetonitrile containing an internalstandard. For the 0 min time point, the reactions were kept on icebefore adding Compound 22 sodium salt. After 5 min on ice, the reactionmixture was terminated by adding 400 μL of acetonitrile containing aninternal standard. Supernatants were transferred to labeled strip tubeswith caps, which were vortexed for 3 min, and then sonicated for anadditional 3 min. The samples were centrifuged for 10 min at 4000 rpmand the supernatants were used for metabolite identification.

Two major metabolites of sodium Compound 22 sodium salt were identifiedin hepatocytes. The taurine conjugate (Compound 99), was detected inhuman, monkey, dog and rat. The glycine conjugate (Compound 100), wasonly detected in human and monkey.

MS/MS fragmentation was used to identify the metabolites. The identityof the taurine conjugate of Compound 22 was confirmed by thecharacteristic m/z=202 peak, corresponding to the(4-chlorophenyl)(phenyl)amino group and the ink=290 peak, correspondingto the(4-((2-oxo-2-(2-sulfonatoethylamino)ethoxy)methyl)cyclohexyl)methylgroup. See FIG. 22 . The identity of the glycine conjugate of Compound22 was confirmed by the characteristic, m/z=487 consistent with anaddition of glycine moiety. Furthermore, the fragmentation pattern alsoshowed the characteristic m/z=202 peak, indicating the(4-chlorophenyl)(phenyl)amino group moiety was intact. See FIG. 23 .

Example 10: In Vivo Metabolism of Sodium2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatein Rats

Three bile-duct cannulated male Sprague-Dawley rats were dosedintravenously (IV) at 2.00 mg/kg. In addition to plasma samples, bileand urine were collected from 0 to 48 hours post-dose.2-(2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetamido)ethanesulfonicacid (the taurine conjugate of Compound 22) (Compound 99) is a majormetabolite of sodium2-(((1r,4r)-4-(((4-chlorophenylxphenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetatein rats. The taurine conjugate of Compound 22 was observed in bile butnot observed in urine.

Example 11: Pharmakinetics in Rats after an Oral Administration of2-(2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetamido)ethanesulfonicAcid (Compound 99)

Male Sprague-Dawley rats (N=3) were given a 1.25 mg/kg oral (P0)administration of2-(2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetamido)ethanesulfonicacid (the taurine conjugate of Compound 22) (Compound 99) formulated in20°4, hydroxypropyl cyclodextrin (HPCD) and dosed at 1.00 mL/kg. Bloodsamples were obtained from 0.100 to 21.0 h post-dose for plasma drugconcentration measurements. Plasma levels of the taurine conjugate ofCompound 22 and2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid (Compound 22) were determined using a selective LC/MS/MS method.Pharmacokinetic parameters were estimated using non-compartmentalpharmacokinetic analysis.

The taurine conjugate of Compound 22 showed minimal exposure and wasconverted to Compound 22 after a 1.25 mg/kg oral dose in rats. Theterminal phase half-lives (T_(1/2)) of Compound 22 and the taurineconjugate of Compound 22 were 3.51 and 3.24 hr, respectively. TheC_(max) of Compound 22 and the taurine conjugate of Compound 22 were0.214 μg/mL at 2.67 hr and 0.00193 μg/mL at 3.33 hr, respectively. TheAUC_(last) values of Compound 22 and the taurine conjugate of Compound22 were 0.935 and 0.0119 hr μg/mL, respectively. See FIG. 24 .

The time to T_(max) (3 h) for the taurine conjugate of Compound 22 wasextended compared to the T_(max) (1.5 h) after a 10 mg/kg oral dose ofCompound 22. See FIG. 25

It is apparent from these data that the taurine conjugate of Compound 22can act as a pro-drug for Compound 22.

Example 12: Excipient Solubility and Compatibility Study of2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid (Compound 22) and Sodium2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate(Compound 22 Sodium Salt)

The solubility of2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)aceticacid (Compound 22) and sodium2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetate(Compound 22 sodium salt) in various excipients was measured. Theresults of the solubility study are presented in the following table.

Solubility (mg/mL) Sodium Salt of Solvents Compound 22 Compound 22 CornOil <0.10 0.93 Safflower oil <0.10 0.82 Labrasol 12.98 54.1 Cremophor RH40 7.82 44.8 Imwitor 742 16.20 37.4 TPGS 1000 2.55 35.0 Gelucire 44/141.61 43.4 PEG400 4.85 44.6 Lauroglycol 90 0.26 46.6 PEG6000 <10 >20Gelucire 50/13 <10 >20

As can be seen from the preceding table, Compound 22 was observed to begenerally more soluble than Compound 22 sodium salt in the excipientstested.

Compound 22 was tested for stability in three of the excipients.Solutions of Compound 22 in Cremophor RH 40, Imwitor 742 and TPGS 1000showed no observable degradation or API assay loss after four weeks in aglass vial at 50° C.

Based in part on the foregoing solubility and stability data, it isapparent that Compound 22 is suitable for formulation in liquid media.

Those skilled in the art will recognize that various modifications,additions, substitutions and variations to the illustrative examples setforth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but not limitedto, printed publications and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

1.-72. (canceled)
 73. A process for the preparation of a compound ofFormula (III):

or a salt form thereof, wherein: R¹ is selected from C₁-C₆alkyl, aryland heteroaryl; each optionally substituted with one or two substituentsselected from: C₁-C₆alkoxy, C₁-C₆alkyl, aryl, C₁-C₆haloalkoxy, C₁-C₆haloalkyl and halogen; R² is selected from: H, C₁-C₆ alkyl and aryl;wherein said aryl is optionally substituted with one or two substituentsselected from: C₁-C₆ alkyl and halogen; and R⁵ is C₁-C₆ alkyl, whereinthe alkyl is optionally substituted; or —OR⁵ is R⁹; R⁹ is a radicalderived from any natural or unnatural amino acid, upon the loss of ahydrogen atom from the α-amino group of said natural or unnatural aminoacid; or R⁹ is —NHCH₂CH₂SO₂H; or R⁹ is —NH—CH(R¹⁰)(R¹¹); R¹⁰ is selectedfrom: H and carboxyl; and R¹¹ is selected from: H and C₁-C₆ alkyl;wherein C₁-C₆ alkyl is optionally substituted with one or twosubstituents such as 4-hydroxyphenyl, amino, carboxamide, carboxyl,guanidino, hydroxyl, imidazolyl, indolyl, methylthio, phenyl,pyrrolidinyl, sulfo and thiol; comprising reacting a compound of Formula(IV):

or a salt from thereof; with a compound of Formula (V):

wherein R⁶ is selected from: C₁-C₆ alkylarylsulfonate, C₁-C₆alkylsulfonate, arylsulfonate, C₁-C₆ haloalkylsulfonate and halogen; inthe presence of a base to form a compound of Formula (III) or a saltform thereof.
 74. The process of claim 73, wherein the R¹ is aryl,optionally substituted with one or two substituents selected from: C₁-C₆alkoxy, C₁-C₆ alkyl, aryl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl andhalogen.
 75. The process of claim 73, wherein the R² is aryl optionallysubstituted with one or two substituents selected from: C₁-C₆ alkyl andhalogen.
 76. The process of claim 73, wherein the R⁵ is tert-butyl. 77.The process of claim 73, wherein the R⁶ is halogen.
 78. The process ofclaim 73, wherein R¹ is aryl optionally substituted with one or twosubstituents selected from: C₁-C₆alkoxy, C₁-C₆alkyl, aryl,C₁-C₆haloalkoxy, C₁-C₆haloalkyl and halogen; R² is aryl is optionallysubstituted with one or two substituents selected from: C₁-C₆alkyl andhalogen; and R⁵ is C₁-C₆ alkyl.
 79. The process of claim 73, wherein thecompound of Formula (IV) is prepared by a process comprising reacting acompound of Formula (VI):

or a salt form thereof; wherein R⁷ is a first leaving group; with acompound of formula (VII):

to form a compound of Formula (IV) or a salt form thereof.
 80. Theprocess of claim 79, wherein the compound of Formula (VI) is prepared bya process comprising reacting a compound of Formula (VIII):

or a salt form thereof; with a compound of formula (IX):

wherein R⁸ is a second leaving group; to form a compound of Formula (VI)or a salt form thereof.